(Aza)indole derivative substituted in position 5, pharmaceutical composition comprising it, intermediate compounds and preparation process therefor

ABSTRACT

An (aza)indole derivative substituted in position 5, of formula (I) in which X, Y, Z, G1, G2, G3, R1, W, and R2 have the meanings given in the description, a pharmaceutical composition comprising it, and also intermediate compounds and a preparation process therefor.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 12/745,356, filed Jun. 18, 2010, which was 371 of InternationalPatent Application No. PCT/EP2008/067622, filed on Dec. 16, 2008, andclaims priority to European Patent Application No. 07425830.2, filed onDec. 28, 2007.

The present invention relates to an (aza)indole derivative substitutedin position 5, to a pharmaceutical composition comprising it, tointermediate compounds and to a preparation process therefor.

More particularly, the present invention relates to an (aza)indolederivative substituted in position 5, which has inhibitory activity onmPGES-1.

It is known that prostaglandins (PG) are oxygenated fatty acidssynthesized and released into the extracellular space, and then into theplasma, urine and other biological fluids.

They are important bioregulators, but also inflammation mediators thatmodulate intracellular reactions and intercellular communication.

The prostaglandins E₂ (PGE₂) have an important physiological role ofregulating renal function, vascular homeostasis, bone remodeling,induction of fever, gastrointestinal function and pregnancy. Besidesthese physiological functions, the PGE₂ prostaglandins behave as potentmediators of acute inflammation (inducing hyperalgesia, vasodilatationand discharge of fluids from vessels: Vane J. R. and Botting R. M. 1997“Anti-inflammatory drugs and their mechanism of action” Inflamm. Res. 47(2): p. 78) and chronic inflammation. Specifically, the PGE₂prostaglandins are particularly abundant in articular inflammatorypathologies. PGE₂ prostaglandins also play a role in pain and are potentpyretic agents (Ayoub S. S. et al., 2004 “Acetaminophen-inducedhypothermia in mice is mediated by a prostaglandin endoperoxide synthase1 gene-derived protein”, PNAS 101: 11165-11169; Ivanov A. et al. 2002“Prostaglandin E₂-synthesizing enzymes in fever: differentialtranscriptional regulation”, Am. J. Physiol. Regul. Integr. Comp.Physiol. 283: R1104-R1117).

The enzyme responsible for the synthesis of PGE₂ prostaglandins isprostaglandin E synthase (PGES), which converts the endoperoxide PGH₂,formed from arachidonic acid by the action of cyclooxygenases, intoPGE₂. The activity of PGES has been found both in the cytosolic fractionand membrane-bound in various types of cells.

Three enzymatic forms have been identified (Kudo I. et al. 2005“Prostaglandin E synthase, a terminal enzyme for prostaglandin E₂biosynthesis”, Journal of Biochemistry and Molecular Biology 38,633-638); among these, microsomal PGES-1 (mPGES-1) is a membrane-boundenzyme that requires glutathione as an essential cofactor for itsactivity.

The expression of mPGES-1 is induced by pro-inflammatory stimuli such asIL-1β or LPS (Proc. Natl. Acad. Sci. 96: 7220, 1999). It is co-localizedtogether with COX-2 on the endoplasmatic reticulum and on the nuclearenvelope (Lazarus M. et al. 2002 “Biochemical characterization of mousemicrosomal prostaglandin E synthase-1 and its colocalization withcyclooxygenase-2 in peritoneal macrophages” Arch. Biochem. Biophys. 397:336; Murakami M. et al. 2000 “Regulation of prostaglandin E2biosynthesis by inducible membrane-associated prostaglandin E2 synthasethat acts in concert with cyclooxygenase-2” J. Biol. Chem. 275: 32783;Yamagata K. et al. 2001 “Coexpression of microsomal-type prostaglandin Esynthase with cyclooxygenase-2 in brain endothelial cells of rats duringendotoxin-induced fever” J. Neurosci. 15; 21(8): 2669-77). Although thetwo enzymes (COX-2 and mPGES-1) have a functional connection andco-expression, their rate of induction differs in a few cellularsystems, indicating different regulatory induction mechanisms (J.Immunol. 167: 469, 2001).

Drugs that inhibit the enzyme COX-2 have been shown to be effective inalleviating inflammation and pain in chronic inflammatory pathologiessuch as arthritis, but their prolonged use may induce tissue damagecaused by an overproduction of cytokines, for instance TNFα and IL-1β(Stichtenoth D. O. 2001 “Microsomal prostaglandin E synthase isregulated by proinflammatory cytokines and glucocorticoids in primaryrheumatoid synovial cells” J. Immunol. 167: 469). In addition, theprolonged use of these drugs is associated with cardiovascular sideeffects. This has led to the withdrawal from the market of a number ofselective COX-2 inhibitors and to a revision of the indications for theentire class of these drugs.

Recent research efforts are directed towards overcoming the side effectsof COX-2 inhibitors by studying mPGES-1 inhibitors for the purpose ofdeveloping drugs that are active in the treatment of inflammation andpain (B. Samuelsson et al. “Membrane Prostaglandin E Synthase-1: A NovelTherapeutic Target” Pharmacol. Rev. 59:207-224, 2007).

In addition, numerous studies have demonstrated that the PGE₂prostaglandins are tumor-promoting factors (L. R. Howe, “Inflammationand breast cancer. Cyclooxygenase/prostaglandin signaling and breastcancer”, Breast cancer research 2007, 9:210, Castellone M. D. et al.2005 “Prostaglandin E₂ promotes colon cancer growth through a novelGs-Axin-B-catenin”, Science 310, 1504-1510; Mehrotra S., et al. 2006“Microsomal prostaglandin E₂ in breast cancer: a potential target fortherapy”, J. Pathol. 208(3): 356-63; Nakano et al. 2006 “Induction ofmacrophagic prostaglandin E2 synthesis by glioma cells” J. Neurosurgery104(4), 574-582) that are involved in angiogenesis, cell proliferationand cell migration functions. Selective FANS and COX-2 inhibitors arealso found to inhibit various types of tumors, including colonrectal,oesophageal, breast, lung and bladder tumors by means of inhibitingPGE₂. PGE₂ prostaglandins derived from COX-2 induce tumor growth bymeans of binding to the actual receptors and activating signals forcontrolling cell proliferation, migration, apoptosis and angiogenesis(Wang D. et al. 2006 “Prostaglandin and cancer” Gut. 55 (1):115-22; HanC. et al. 2006 “Prostaglandin E₂ receptor EP1 transactivates EGFR/METreceptor tyrosine kinases and enhances invasiveness in humanhepatocellular carcinoma cells”, Journal of Cellular Physiology 207:261-270).

An (aza)indole derivative substituted in position 5 that has selectiveinhibitory activity on mPGES-1 has now been found. The wording“(aza)indole derivative” is intended to represent a compound withinformula (I) hereinbelow, wherein the basic nucleus, represented by anindole ring, can have one or more carbon atoms in the 4, 6, and 7position optionally replaced with a nitrogen atom and a single or doublebond between the carbon atoms in the 2- and 3-position.

In a first aspect, the present invention relates to an (aza)indolederivative substituted in position 5, of formula (I):

in which:

-   X is a halogen atom or a (C₁-C₃)alkyl, trifluoromethyl, nitro,    amino, cyano, di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, phenyl or    (C₁-C₃)alkylphenyl group;-   Y and Z, which may be identical or different, are a hydrogen or    halogen atom, or a (C₁-C₃)alkyl, trifluoromethyl, nitro, amino,    di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, phenyl, COOH,    (C₁-C₃)alkyl-COOH, (C₂-C₃)alkenyl-COOH, COOR, wherein R is a linear    or branched (C₁-C₆)alkyl or hydroxyalkyl group, CONH₂, SO₂CH₃,    SO₂NHCH₃ or NHSO₂CH₃ group;-   G1, G2, and G3, which may be identical or different, are a nitrogen    atom or a CH group;-   R1 is a (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₆)alkylOR^(I),    (CH₂)_(n)NR^(II)R^(III), (CH₂)_(n)CONR^(II)R^(III),    (CH₂)_(n)COR^(I), (CH₂)_(n)COOR^(II), (CH₂)_(n)OCOR^(I), SO₂R^(I),    (CH₂)_(n)NR^(II)SO₂R^(I), (CH₂)_(n)SO₂R^(I) group, optionally    substituted with 1 to 3 hydroxy groups, wherein n is an integer from    1 to 6, R^(I) is a (C₁-C₃)alkyl, or (C₁-C₃)alkylOH group, and R^(II)    and R^(III), which may be identical or different, are a hydrogen    atom or a (C₁-C₃)alkyl group;-   W is a σ bond, or a (C₁-C₆)alkyl, (C₂-C₆)alkenyl, O(C₁-C₆)alkyl,    O(C₂-C₆)alkenyl, C(O)NH, (CH₂)_(p)CO(CH₂)_(q), or    (CH₂)_(p)C(OH)(CH₂)_(q), group, wherein p and q, which may be    identical or different, are an integer from 0 to 3;-   R2 is a phenyl, pyridine or (C₃-C₇)cycloalkyl group, optionally    substituted with 1 to 3 substituents, which may be identical or    different, represented by a L-M group, wherein L is a σ bond, or a    (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkinyl, O(C₁-C₆)alkyl,    O(C₂-C₆)alkenyl, O(C₂-C₆)alkinyl group, and M is a hydrogen or    halogen atom, or a OH, CF₃, NO₂, CN, COOR^(II), SO₂NHR^(II),    CH₂CONR^(II)R^(III), NR^(II)R^(III), SO₂R^(IV), NHSO₂R^(IV),    POR^(IV)R^(V), or OPOR^(IV)R^(V) group, wherein R^(II) and R^(III),    which may be identical or different, have the meaning above, and    R^(IV) and R^(V), which may be identical or different, are a    (C₁-C₃)alkyl group,    provided that-   when G1, G2, and G3 are all a CH group, R1 is a (C₁-C₆)alkyl or    (C₃-C₇)cycloalkyl group, optionally substituted with 1 to 3 hydroxy    groups, W is a σ bond, and the bond between the carbon atoms in the    2 and 3 position is a double bond,-   R2 is not a phenyl or pyridine group, optionally substituted with 1    to 3 substituents, which may be identical or different, selected    from halogen, (C₁-C₆)alkyl optionally substituted with a hydroxy    group, trifluoromethyl, nitro, amino, di(C₁-C₃)alkylamino, hydroxy,    (C₁-C₃)alkoxy, COOH, COOR^(II), SO₂CH₃, SO₂NHCH₃, NHSO₂CH₃,    POR^(IV)R^(V), OPOR^(IV)R^(V), (C₁-C₆)alkyl-COOH, and    (C₂-C₆)alkenyl-COOH;    and provided that    when G1 is N, and G2 and G3 are a CH group, R2 is not a divalent    aromatic group substituted with one L-M group represented by    O(C₁-C₆)alkyl, O(C₂-C₆)alkenyl, and O(C₂-C₆)alkinyl group;    and the physiologically acceptable addition salts, stereoisomers,    enantiomers, hydrates, solvates and polymorphic forms thereof.

The dotted line between the carbon atoms in the 2 and 3 position meansthat such a bond can be a single or a double bond. The chain of thevarious alkyl groups that may be present in the compound of formula (I)may be linear or branched.

In the case of certain substituents, the compound of formula (I)according to the present invention may contain an asymmetric carbon atomand may thus be in the form of stereoisomers and enantiomers. Typicalexamples of such substituents are 2-butanol, 2-methylbutyl, 2-butenoicacid, 2-methylpropanoic acid and 1,2-pentane diol.

Preferably, the halogen is bromine, chlorine or fluorine.

Preferred meanings of X are halogen, (C₁-C₃)alkyl, trifluoromethyl,nitro, cyano and (C₁-C₃)alkoxy. Particularly preferred meanings of X areCl, Br, F, trifluoromethyl and nitro.

Preferred meanings of Y and Z are H, halogen, nitro, COOH, (C₁-C₃)alkyl,trifluoromethyl and (C₁-C₃)alkoxy. Particularly preferred meanings of Yand Z are H, Cl, Br, F, trifluoromethyl, nitro, COOH, methyl, ethyl,methoxy and ethoxy.

Preferred meanings of R1 are a (C₁-C₃)alkyl, (C₁-C₃)alkylOR^(I),(CH₂)_(n)NR^(II)R^(III), (CH₂)_(n)CONR^(II)R^(III), (CH₂)_(n)COR^(I),(CH₂)_(n)COOR^(II), (CH₂)_(n)OCOR^(I), SO₂R^(I),(CH₂)_(n)NR^(II)SO₂R^(I), (CH₂)_(n)SO₂R^(I) group, optionallysubstituted with 1 to 3 hydroxy groups, wherein n is an integer from 1to 4, R^(I) is a (C₁-C₃)alkyl or (C₁-C₃)alkylOH group, and R^(II) andR^(III), which may be identical or different, are a hydrogen atom or a(C₁-C₃)alkyl group.

Particularly preferred meanings of R1 are a (C₁-C₃)alkyl,(C₁-C₃)alkylOR^(I), (CH₂)_(n)CONR^(II)R^(III), (CH₂)_(n)COR^(I),(CH₂)_(n)COOR^(II), (CH₂)_(n)OCOR^(I), SO₂R′, (CH₂)_(n)NR^(II)SO₂R^(I),(CH₂)_(n)SO₂R^(I) group, optionally substituted with 1 to 3 hydroxygroups, wherein n is an integer from 1 to 3, R^(I) is a CH₃, C₂H₅,CH₂OH, or C₂H₄OH group, and R^(II) and R^(III), which may be identicalor different, are a hydrogen atom or a CH₃, C₂H₅ group.

Preferred meanings of W are a σ bond, or a (C₁-C₃)alkyl, (C₂-C₄)alkenyl,O(C₁-C₃)alkyl, O(C₂-C₃)alkenyl, C(O)NH, (CH₂)_(p)CO(CH₂)_(q), or(CH₂)_(p)C(OH)(CH₂)_(q) group, wherein p and q, which may be identicalor different, are an integer from 1 to 3.

Particularly preferred meanings of W are a σ bond, or a CH₂, C₂H₄,CH═CH, OCH₂, OC₂H₄, OCH═CH, C(O)NH, (CH₂)_(p)CO(CH₂)_(q), or(CH₂)_(p)C(OH)(CH₂)_(q) group, wherein p and q, which may be identicalor different, are an integer from 1 to 2.

Preferred meanings of R2 are a phenyl, pyridine or (C₃-C₇)cycloalkylgroup, optionally substituted with 1 to 2 substituents, which may beidentical or different, represented by a L-M group, wherein L is a abond, or a (C₁-C₃)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkinyl, O(C₁-C₃)alkyl,O(C₂-C₄)alkenyl, O(C₂-C₄)alkinyl group, and M is a hydrogen or halogenatom, or a CF₃, CN, COOR^(II), SO₂NHR^(II), CH₂CONR^(II)R^(III),NR^(II)R^(III), SO₂R^(IV), NHSO₂R^(IV), POR^(IV)R^(V), or OPOR^(IV)R^(V)group, wherein R^(II) and R^(III), which may be identical or different,are a hydrogen atom or a (C₁-C₃)alkyl group, and R^(IV) and R^(V), whichmay be identical or different, are a (C₁-C₃)alkyl group.

Particularly preferred meanings of R2 is a phenyl, pyridine or(C₃-C₇)cycloalkyl group, optionally substituted with 1 substituentrepresented by a L-M group, wherein L is a G bond, or a CH₂, C₂H₄,CH═CH, C≡C, OCH₂, OC₂H₄, OCH═CH, OC≡C group, and M is a hydrogen orhalogen atom, or a CF₃, CN, COOR^(II), SO₂NHR^(II), CH₂CONR^(II)R^(III),NR^(II)R^(III), SO₂R^(IV), NHSO₂R^(IV), POR^(IV)R^(V), or OPOR^(IV)R^(V)group, wherein R^(II) and R^(III), which may be identical or different,are a hydrogen atom or a CH₃, C₂H₅ group, and R^(IV) and R^(V), whichmay be identical or different, are a CH₃ or C₂H₅ group.

A first particularly preferred meaning of the group W—R2 is where W is aσ bond, or a CH₂ or C₂H₄ group and R2 is a phenyl group optionallysubstituted with 1 to 3 substituents, which may be identical ordifferent, selected from Br, Cl, and F atom, and CH₃, C₂H₅, OCH₃, OC₂H₅,CN, CH₂CN, and CH₂CONH₂ group.

A second particularly preferred meaning of the group W—R2 is where W isa σ bond, or a CH₂ or C₂H₄ group and R2 is a pyridine group optionallysubstituted with 1 to 3 substituents, which may be identical ordifferent, selected from Br, Cl, and F atom, and CH₃, C₂H₅, OCH₃, OC₂H₅,CN, CH₂CN, and CH₂CONH₂ group.

A third particularly preferred meaning of the group W—R2 is where W is aσ bond, or a CH₂ or C₂H₄ group and R2 is a cyclohexyl group optionallysubstituted with 1 to 3 substituents, which may be identical ordifferent, selected from Br, Cl, and F atom, and CH₃, C₂H₅, OCH₃, OC₂H₅,CN, CH₂CN, and CH₂CONH₂ group.

Depending on the nature of the substituents, the compound of formula (I)may form addition salts with physiologically acceptable organic ormineral acids or bases.

Typical examples of physiologically acceptable mineral acids arehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid andnitric acid.

Typical examples of suitable physiologically acceptable organic acidsare acetic acid, ascorbic acid, benzoic acid, citric acid, fumaric acid,lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-toluenesulfonic acid, benzensulfonic acid, succinic acid, tannicacid and tartaric acid.

Typical examples of suitable physiologically acceptable mineral basesare: ammonia, calcium, magnesium, sodium and potassium.

Typical examples of suitable physiologically acceptable organic basesare: arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,N-methylglucamine, glucamine, glucosamine, histidine,N-(2-hydroxyethyl)piperidine, N-(2-hydroxyethyl)pyrrolidine,isopropylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, theobromine, triethylamine, trimethylamine, tripropylamineand tromethamine.

In a second aspect, the present invention relates to a process forpreparing an (aza)indole derivative substituted in position 5, offormula (I):

in which X, Y, Z, G1, G2, G3, W, R1 and R2 have the meanings givenabove,

-   -   and the physiologically acceptable addition salts,        stereoisomers, enantiomers, hydrates, sulfates and polymorphic        forms thereof,    -   a) by reacting a compound of formula (II):

-   -   in which    -   X, Y and Z have the meanings given above, and    -   Q is a halogen atom or a hydroxy group,    -   with a compound of formula (III):

-   -   in which    -   G1, G2, G3, R1, R2 and W have the meanings given above,    -   to give a compound of formula (I):

-   -   in which    -   X, Y, Z, G1, G2, G3, R1, R2 and W have the meanings given above,        and    -   b) forming, if so desired, a physiologically acceptable addition        salt of the compound of formula (I) from step (a).

According to a first embodiment, the abovementioned step (a) isperformed by reacting a compound of formula (II) in which Q is Cl withan amine of formula (III) in the presence of a suitable acid acceptoraccording to standard techniques.

According to a second embodiment, the abovementioned step (a) isperformed by reacting a compound of formula (II) in which Q is OH withan amine of formula (III) in the presence of a suitable coupling agentaccording to standard techniques.

Further, the reaction of step (a) can also be conducted in solid phaseby preliminary linking the compound of formula (III) to a preparativeresin, such as, for example PL-FMP Resin, manufactured by from PolymerLaboratories. In this case, a cleavage step, in which the resultingcompound of formula (I) is removed from the resin is made after step(a). Such a cleavage step is made with conventional techniques, such as,for example, treatment with trifluoroacetic acid.

When the compound of formula (I) is intended to have a single bondbetween the carbon atoms in the 2- and 3-position, a reduction step ismade after step (a). Such a reduction step is made with conventionaltechniques, such as, for example, treatment with tin in the presence ofa strong acid.

When R1 is represented by a (CH₂)nCOOR^(II) group, and R^(II) is analkyl group, the corresponding acid, wherein R^(II) is a hydrogen atom,may be obtained by hydrolysis, according to standard techniques, suchas, for example, in the presence of a strong base like NaOH.

The intermediate compounds of formula (III) are novel.

According to a third aspect, the present invention also relates to acompound of formula (III):

wherein

-   G1, G2, and G3, which may be identical or different, are a nitrogen    atom or a CH group;-   R1 is a (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₆)alkylOR^(I),    (CH₂)_(n)CONR^(II)R^(III), (CH₂)_(n)COR^(I), (CH₂)_(n)COOR^(II),    (CH₂)_(n)OCOR^(I), SO₂R^(I), (CH₂)_(n)NR^(II)SO₂R^(I),    (CH₂)_(n)SO₂R^(I) group, optionally substituted with 1 to 3 hydroxy    groups, wherein n is an integer from 1 to 6, R^(I) is a    (C₁-C₃)alkyl, or (C₁-C₃)alkylOH group, and R^(II) and R^(III), which    may be identical or different, are a hydrogen atom or a (C₁-C₃)alkyl    group;-   W is a σ bond, or a (C₁-C₆)alkyl, (C₂-C₆)alkenyl, O(C₁-C₆)alkyl,    O(C₂-C₆)alkenyl, C(O)NH, (CH₂)_(p)CO(CH₂)_(q), or    (CH₂)_(p)C(OH)(CH₂)_(q), group, wherein p and q, which may be    identical or different, are an integer from 0 to 3; and-   R2 is a phenyl, pyridine or (C₄-C₇)cycloalkyl group, optionally    substituted with 1 to 3 substituents, which may be identical or    different, represented by a L-M group, wherein L is a σ bond, or a    (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkinyl, O(C₁-C₆)alkyl,    O(C₂-C₆)alkenyl, O(C₂-C₆)alkinyl group, and M is a hydrogen or    halogen atom, or a OH, CF₃, NO₂, CN, COOR^(II), SO₂NHR^(II),    CH₂CONR^(II)R^(III), NR^(II)R^(III), SO₂R^(IV), NHSO₂R^(IV),    POR^(IV)R^(V), or OPOR^(IV)R^(V) group, wherein R^(II) and R^(III),    which may be identical or different, have the meaning above, and    R^(IV) and R^(V), which may be identical or different, are a    (C₁-C₃)alkyl group,    provided that-   when G1, G2, and G3 are all a CH group, R1 is a (C₁-C₆)alkyl or    (C₃-C₇)cycloalkyl group, optionally substituted with 1 to 3 hydroxy    groups, W is a σ bond, and the bond between the carbon atoms in the    2 and 3 position is a double bond,-   R2 is not a phenyl or pyridine group, optionally substituted with 1    to 3 substituents, which may be identical or different, selected    from halogen, (C₁-C₆)alkyl optionally substituted with a hydroxy    group, trifluoromethyl, nitro, amino, di(C₁-C₃)alkylamino, hydroxy,    (C₁-C₃)alkoxy, COOH, COOR^(II), SO₂CH₃, SO₂NHCH₃, NHSO₂CH₃,    POR^(IV)R^(V), (C₁-C₆)alkyl-COOH, and (C₂-C₆)alkenyl-COOH    and provided that    when G1 is N, and G2 and G3 are a CH group, R2 is not a divalent    aromatic group substituted with one L-M group represented by    O(C₁-C₆)alkyl, O(C₂-C₆)alkenyl, and O(C₂-C₆)alkinyl group.

Preferred meanings of R1 is a (C₁-C₃)alkyl, (C₁-C₃)alkylOR^(I),(CH₂)_(n)CONR^(II)R^(III), (CH₂)_(n)COR^(I), (CH₂)_(n)COOR^(II),(CH₂)_(n)OCOR^(I), SO₂R^(I), (CH₂)_(n)NR^(II)SO₂R^(I), (CH₂)_(n)SO₂R^(I)group, optionally substituted with 1 to 3 hydroxy groups, wherein n isan integer from 1 to 4, R^(I) is a (C₁-C₃)alkyl or (C₁-C₃)alkylOH group,and R^(II) and R^(III), which may be identical or different, are ahydrogen atom or a (C₁-C₃)alkyl group.

Particularly preferred meanings of R1 is a (C₁-C₃)alkyl,(C₁-C₃)alkylOR^(I), (CH₂)_(n)CONR^(II)R^(III), (CH₂)_(n)COR^(I),(CH₂)_(n)COOR^(II), (CH₂)_(n)OCOR^(I), SO₂R^(I),(CH₂)_(n)NR^(II)SO₂R^(I), (CH₂)_(n)SO₂R^(I) group, optionallysubstituted with 1 to 3 hydroxy groups, wherein n is an integer from 1to 3, R^(I) is a CH₃, C₂H₅, CH₂OH, or C₂H₄OH group, and R^(II) andR^(III), which may be identical or different, are a hydrogen atom or aCH₃, C₂H₅ group.

Preferred meanings of W are a bond, or a (C₁-C₃)alkyl, (C₂-C₄)alkenyl,O(C₁-C₃)alkyl, O(C₂-C₃)alkenyl, C(O)NH, (CH₂)_(p)CO(CH₂)_(q), or(CH₂)_(p)C(OH)(CH₂)_(q) group, wherein p and q, which may be identicalor different, are an integer from 1 to 3.

Particularly preferred meanings of W are a bond, or a CH₂, C₂H₄, CH═CH,OCH₂, OC₂H₄, OCH═CH, C(O)NH, (CH₂)_(p)CO(CH₂)_(q), or(CH₂)_(p)C(OH)(CH₂)_(q) group, wherein p and q, which may be identicalor different, are an integer from 1 to 2.

Preferred meanings of R2 is a phenyl, pyridine or (C₄-C₇)cycloalkylgroup, optionally substituted with 1 to 2 substituents, which may beidentical or different, represented by a L-M group, wherein L is a abond, or a (C₁-C₃)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkinyl, O(C₁-C₃)alkyl,O(C₂-C₄)alkenyl, O(C₂-C₄)alkinyl group, and M is a hydrogen or halogenatom, or a CF₃, CN, COOR^(II), SO₂NHR^(II), CH₂CONR^(II)R^(III),NR^(II)R^(III), SO₂R^(IV), NHSO₂R^(IV), POR^(IV)R^(V), or OPOR^(IV)R^(V)group, wherein R^(II) and R^(III), which may be identical or different,are a hydrogen atom or a (C₁-C₃)alkyl group, and R^(IV) and R^(V), whichmay be identical or different, are a (C₁-C₃)alkyl group.

Particularly preferred meanings of R2 is a phenyl, pyridine or(C₄-C₇)cycloalkyl group, optionally substituted with 1 substituentrepresented by a L-M group, wherein L is a σ bond, or a CH₂, C₂H₄,CH═CH, C≡C, OCH₂, OC₂H₄, OCH═CH, OC≡C group, and M is a hydrogen orhalogen atom, or a CF₃, CN, COOR^(II), SO₂NHR^(II), CH₂CONR^(II)R^(III),NR^(II)R^(III), SO₂R^(IV), NHSO₂R^(IV), POR^(IV)R^(V), or OPOR^(IV)R^(V)group, wherein R^(II) and R^(III), which may be identical or different,are a hydrogen atom or a CH₃, C₂H₅ group, and R^(IV) and R^(V), whichmay be identical or different, are a CH₃ or C₂H₅ group.

A first particularly preferred meaning of the group W—R2 is where W is aσ bond, or a CH₂ or C₂H₄ group and R2 is a phenyl group optionallysubstituted with 1 to 3 substituents, which may be identical ordifferent, selected from Br, Cl, and F atom, CH₃, C₂H₅, OCH₃, OC₂H₅, CN,CH₂CN, and CH₂CONH₂ group.

A second particularly preferred meaning of the group W—R2 is where W isa σ bond, or a CH₂ or C₂H₄ group and R2 is a pyridine group optionallysubstituted with 1 to 3 substituents, which may be identical ordifferent, selected from Br, Cl, and F atom, CH₃, C₂H₅, OCH₃, OC₂H₅, CN,CH₂CN, and CH₂CONH₂ group.

A third particularly preferred meaning of the group W—R2 is where W is aσ bond, or a CH₂ or C₂H₄ group and R2 is a cyclohexyl group optionallysubstituted with 1 to 3 substituents, which may be identical ordifferent, selected from Br, Cl, and F atom, CH₃, C₂H₅, OCH₃, OC₂H₅, CN,CH₂CN, and CH₂CONH₂ group.

The investigations on the biological properties of the compound offormula (I) according to the present invention demonstrated that it hasan unexpected selective property of inhibiting mPGES-1 and pronouncedanti-nociceptive activity in inflammatory pain.

In a fourth aspect, the present invention thus relates to apharmaceutical composition containing an effective amount of a compoundof formula (I), or of a physiologically acceptable addition salt,stereoisomer, enantiomer, hydrate, solvate or polymorphic form thereof,and at least one pharmaceutically acceptable inert ingredient.

In the present description and in the claims, the term “effectiveamount” refers to an amount that gives an appreciable improvement in atleast one symptom or parameter of a specific disorder.

The pharmaceutical composition according to the present invention willbe used in the treatment or prevention of disorders associated with theproduction of prostaglandin E₂ (PGE₂), for instance inflammatoryprocesses, pain, tumors, neurodegenerative disorders andatherosclerosis.

Advantageously, the pharmaceutical composition according to the presentinvention will be used in the treatment of pain in chronic inflammatorypathologies such as arthritis, or of tumors, particularly colorectal,oesophageal, breast, lung and bladder tumors.

Preferably, the pharmaceutical compositions of the present invention areprepared in suitable dosage forms comprising an effective dose of atleast one compound of formula (I) or of a physiologically acceptableaddition salt, stereoisomer, enantiomer, hydrate, solvate or polymorphicform thereof, and at least one pharmaceutically acceptable inertingredient.

Examples of suitable dosage forms are tablets, capsules, coated tablets,granules, solutions and syrups for oral administration; creams,ointments and antiseptic plasters for topical administration;suppositories for rectal administration and sterile solutions foradministration by injection or aerosol or ophthalmic administration.

The dosage forms may also contain other conventional ingredients, forinstance: preserving agents, stabilizers, surfactants, buffers, saltsfor regulating the osmotic pressure, emulsifiers, sweeteners, colorants,flavorings and the like.

If required for particular therapies, the pharmaceutical composition ofthe present invention may contain other pharmacologically activeingredients whose simultaneous administration is beneficial.

The amount of compound of formula (I) or of a physiologically acceptableaddition salt, stereoisomer, enantiomer, hydrate, solvate or polymorphicform thereof, and at least one pharmaceutically acceptable inertingredient in the pharmaceutical composition of the present inventionmay vary within a wide range depending on known factors, for instancethe type of disease to be treated, the severity of the disease, the bodyweight of the patient, the dosage form, the chosen route ofadministration, the number of daily administrations and the efficacy ofthe chosen compound of formula (I). However, the optimum amount may beeasily and routinely determined by a person skilled in the art.

Typically, the amount of compound of formula (I) or of a physiologicallyacceptable addition salt, stereoisomer, enantiomer, hydrate, solvate orpolymorphic form thereof, and at least one pharmaceutically acceptableinert ingredient in the pharmaceutical composition of the presentinvention will be such that it provides a level of administration ofbetween 0.0001 and 100 mg/kg/day and even more preferably between 0.01and 10 mg/kg/day.

Clearly, the pharmaceutical formations of the present invention do notnecessarily need to contain the entire amount of the compound of formula(I) since the said effective amount may be added by means ofadministration of a plurality of doses of the pharmaceutical compositionof the present invention.

The dosage forms of the pharmaceutical composition of the presentinvention may be prepared according to techniques that are well known topharmaceutical chemists, including mixing, granulation, compression,dissolution, sterilization and the like.

The examples that follow serve to further illustrate the inventionwithout, however, limiting it.

EXAMPLE 1 Preparation of Intermediate Compounds a)1-ethyl-2-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

To a solution of 2-amino-3-bromo-5-nitropyridine (1.2 g, 5.5 mmol) inanhydrous THF (23 ml), PdCl₂ (52 mg, 0.29 mmol), 1,1′-Bis(di-tert-butylphosphino)ferrocene (D-tBPF, 0.17 g, 0.39 mmol), diisopropylamine (0.81g, 8.0 mmol), and CuI (22 mg, 0.11 mmol) were added while stirring. Tothis mixture 4-ethynyltoluene (1.0 ml, 7.9 mmol) was added dropwise over2.25 hours. The mixture thus obtained was filtered under vacuum throughCelite, the residue washed several times with EtOAc.

After evaporation of the solvent, the residue was purified by columnchromatography on silica gel (Et₂O/n-hexane, Et₂O 30%→60%) to give5-nitro-3-(phenylethynyl)pyridin-2-amine as yellow solid:

¹H-NMR (CDCl₃): 8.93 (d, J=2.7 Hz, 1H); 8.36 (d, J=2.7 Hz, 1H); 7.42(AA′ of AA′BB′ system, 2H); 7.19 (BB′ of AA′BB′ system, 2H); 5.85 (bs,2H); 2.39 (s, 3H).

To a suspension of potassium ter-butoxide (0.41 g, 3.7 mmol) inanhydrous DMF (5 ml) a solution of5-nitro-3-(phenylethynyl)pyridin-2-amine (0.70 g, 2.8 mmol), in DMF (25ml) was added dropwise while stirring at room temperature. After 1.5days, iodoethane (0.38 ml, 4.7 mmol) was added and the whole stirred foradditional 1.5 days. To the reaction H₂O (50 ml) and EtOAc (100 ml) werethen added. The mixture was poured into a separatory funnel, the organiclayer separated, the aqueous one thoroughly extracted with EtOAc (50 ml)and combined organic layers washed with brine (2×100 ml). The organicsolvent was removed by evaporation under reduced pressure and theresidue was purified by column chromatography on silica gel(Et₂O/n-hexane, Et₂O 10%→20%) to give1-ethyl-2-(4-methylphenyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine:

¹H-NMR (CDCl₃): 9.21 (d, J=2.7 Hz, 1H); 8.71 (d, J=2.7 Hz, 1H); 7.40(AA′ of AA′BB′ system, 2H); 7.32 (BB′ of AA′BB′ system, 2H); 6.60 (s,1H); 4.41 (q, J=7.2 Hz, 2H); 2.45 (s, 3H); 1.31 (t, J=7.2 Hz, 3H)

A solution of1-ethyl-2-(4-methylphenyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.36 g,1.3 mmol) in a EtOAc/EtOH (absolute)=4:7 mixture (110 ml) washydrogenated in H₂ atmosphere with the presence of 10% Pd(C) (110 mg)for 2 h. The residue was filtered under vacuum through Celite to removethe catalyst and the solvent evaporated to give crude1-ethyl-2-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine which wasused without any further purification:

¹H-NMR (CDCl₃): 7.91 (d, J=3.0 Hz, 1H); 7.39 (AA′ of AA′BB′ system, 2H);7.32-7.18 (m, 3H); 6.25 (s, 1H); 4.30 (q, J=7.5 Hz, 2H); 3.32 (bs, 2H);2.41 (s, 3H); 1.27 (t, J=7.5 Hz, 3H).

b) 1-isopropyl-2-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

The process described above in Example 1a) was used, except thatisopropylbromide was used instead of iodoethane.

1-isopropyl-2-(4-methylphenyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine:

¹H-NMR (CDCl₃): 9.18 (d, J=2.4 Hz, 1H); 8.67 (d, J=2.4 Hz, 1H); 7.34(AA′BB′ system, 4H); 6.52 (s, 1H); 4.70 (ept., J=6.9 Hz, 1H); 2.45 (s,3H); 1.70 (d, J=6.9 Hz, 6H)

1-isopropyl-2-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine:

¹H-NMR (CDCl₃): 7.85 (d, J=1.4 Hz, 1H); 7.27 (AA′ of AA′BB′ system, 2H);7.16-7.05 (m, 3H); 6.11 (s, 1H); 4.56 (ept., J=7.0 Hz, 1H); 3.85 (bs,2H); 2.33 (s, 3H), 1.59 (d, J=7.0 Hz, 6H).

c) 1-(2-methoxyethyl)-2-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

The process described above in Example 1a) was used, except that2-methoxyethylbromide was used instead of iodoethane.1-(2-methoxyethyl)-2-(4-methylphenyl)-5-nitro-1H-pyrrolo[2,3-]pyridine:

¹H-NMR (CDCl₃): 9.21 (d, J=2.4 Hz, 1H); 8.71 (d, J=2.4 Hz, 1H); 7.49(AA′ of AA′BB′ system, 2H); 7.32 (BB′ of AA′BB′ system, 2H); 6.62 (s,1H); 4.54 (t, J=5.6 Hz, 2H); 3.70 (t, J=5.6 Hz, 2H); 3.19 (s, 3H); 2.45(s, 3H).

1-(2-methoxyethyl)-2-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine:

¹H-NMR (CDCl₃): 7.89 (d, J=2.7 Hz, 1H); 7.46 (AA′ of AA′BB′ system, 2H);7.25 (BB′ of AA′BB′ system, 2H); 7.19 (d, J=2.4 Hz, 1H); 6.27 (s, 1H);4.42 (t, J=6.0 Hz, 2H); 3.68 (t, J=6.0 Hz, 2H); 3.40 (bs, 1H); 3.17 (s,3H); 2.40 (s, 3H).

d) 1-ethyl-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

The process described above in Example 1a) was used, except that1-ethynyl-4-fluorobenzene was used instead of 4-ethynyltoluene.

3-[(4-fluorophenyl)ethynyl]-5-nitropyridin-2-amine:

¹H-NMR (CDCl₃/CD₃OD): 8.78 (d, J=2.3 Hz, 1H); 8.24 (d, J=2.3 Hz, 1H);7.43 (m, 2H); 6.97 (m, 2H), 2.05 (s, 3H).

1-ethyl-2-(4-fluorophenyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine

¹H-NMR (CDCl₃): 9.30 (d, J=2.5 Hz, 1H); 8.80 (d, J=2.5 Hz, 1H); 7.60 (m,2H); 7.30 (m, 2H); 6.70 (s, 1H); 4.48 (q, J=7.6 Hz, 2H); 1.39 (t, J=7.6Hz 3H)

1-ethyl-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

¹H-NMR (CDCl₃): 7.90 (d, J=2.4 Hz, 1H); 7.42 (m, 2H); 7.25-7.05 (m, 3H),6.21 (s, 1H); 4.24 (q, J=7.2 Hz, 2H); 3.50 (bs, 2H); 1.22 (t, J=7.2 Hz,3H)

e)2-(4-fluorophenyl)-1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

The process described above in Example 1a) was used, except that1-ethynyl-4-fluorobenzene and 2-methoxyethylbromide were used instead of4-ethynyltoluene and iodoethane, respectively.

2-(4-fluorophenyl)-1-(2-methoxyethyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine:

¹H-NMR (CDCl₃): 9.23 (d, J=2.6 Hz, 1H); 8.74 (d, J=2.6 Hz, 1H);7.90-7.20 (2m, 5H); 6.64 (s, 1H); 4.51 (t, J=5.6 Hz, 2H); 3.75 (t, J=5.6Hz, 2H); 3.20 (s, 3H);

2-(4-fluorophenyl)-1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-5-amine:

¹H-NMR (CDCl₃): 8.00 (d, J=2.2 Hz, 1H); 7.63 (m, 2H); 7.40-7.10 (m, 3H),6.34 (s, 1H); 4.47 (t, J=5.8 Hz, 2H); 3.80 (t, J=5.8 Hz, 4H); 3.25 (s,3H).

f) ethyl 4-(5-amino-2-phenyl-1H-indol-1-yl)butanoate

To a solution of 2-phenyl-5-nitroindole (prepared as described in J.Org. Chem. (1966), 31(1), 65-9) (1.5 g; 6.3 mmol) in CH₃CN (50 ml) wasadded K₂CO₃ (1.7 g; 12.6 mmol). To the mixture thus obtained was thenadded dropwise ethyl 4-bromobutanoate (3.3 g; 16 mmol) and the resultingmixture was heated to 120° C. under stirring for 18 hours. Aftercooling, the mixture was poured into water (500 ml) and the crudeproduct was filtered, dried under vacuum to give ethyl4-(5-nitro-2-phenyl-1H-indol-1-yl)butanoate which was used in thefollowing reaction without any further purification.

¹H-NMR (DMSO-d₆) 1.08 (t, J=7.16 Hz, 3H); 1.80 (quin, J=7.23 Hz, 2H);2.15 (t, J=7.00 Hz, 2H); 3.91 (q, J=7.02 Hz, 2H); 4.34 (t, J=7.31 Hz,2H); 6.84 (s, 1H); 7.47-7.62 (m, 5H); 7.80 (d, J=9.06 Hz, 1H); 8.08 (dd,J=9.21, 2.19 Hz, 1H); 8.59 (d, J=2.34 Hz, 1H).

To a suspension of 10% Pd/C (67 mg, 0.06 mmol) in 95% ethanol (50 ml) asolution of 4-(5-nitro-2-phenyl-1H-indol-1-yl)butanoate (2.2 g; 6 mmol)in 95 ethanol (100 ml) was added (0.1 g; 0.1 mmol) and the mixtureunderwent hydrogenation in a Parr hydrogenator (H₂, 30 psi) for 4 hours.

The residue was filtered under vacuum through Celite to remove thecatalyst and the solvent evaporated to give crude ethyl4-(5-amino-2-phenyl-1H-indol-1-yl)butanoate which was used without anyfurther purification.

¹H NMR (DMSO-d₆) 1.09 (t, J=7.16 Hz, 3H); 1.78 (quin, J=7.16 Hz, 2H);2.09 (t, J=7.16 Hz, 2H); 3.92 (q, J=7.21 Hz, 2H); 4.20 (t, J=7.31 Hz,2H); 6.44 (s, 1H); 6.87 (dd, J=8.62, 2.19 Hz, 1H); 7.14 (d, J=2.05 Hz,1H); 7.35-7.59 (m, 6H); 8.08 (br. s., 2H).

g) ethyl 3-(5-amino-2-phenyl-1H-indol-1-yl)propanoate

The process described above in Example 1f) was used, except that ethyl3-bromopropanoate was used instead of ethyl 4-bromobutanoate.

ethyl 3-(5-nitro-2-phenyl-1H-indol-1-yl)propanoate

¹H NMR (DMSO-d₆) 1.02 (t, J=7.02 Hz, 3H); 2.61 (t, J=7.31 Hz, 2H); 3.88(q, J=7.02 Hz, 2H); 4.57 (t, J=7.16 Hz, 2H); 6.83 (s, 1H); 7.46-7.65 (m,5H); 7.80 (d, J=9.06 Hz, 1H); 8.08 (dd, J=9.06, 2.34 Hz, 1H); 8.57 (d,J=2.34 Hz, 1H).

ethyl 3-(5-amino-2-phenyl-1H-indol-1-yl)propanoate

¹H NMR (DMSO-d₆) 1.05 (t, J=7.16 Hz, 3H); 2.54 (br. s., J=7.50, 7.50 Hz,2H); 3.90 (q, J=7.02 Hz, 2H); 4.36 (t, J=7.31 Hz, 2H); 4.55 (br. s.,2H); 6.24 (s, 1H); 6.57 (dd, J=8.62, 2.19 Hz, 1H); 6.70 (d, J=2.05 Hz,1H); 7.21 (d, J=8.77 Hz, 1H); 7.34-7.55 (m, 5H).

h) ethyl (5-amino-2-phenyl-1H-indol-1-yl)acetate

The process described above in Example 1f) was used, except that ethyl2-bromoacetate was used instead of ethyl 4-bromobutanoate.

ethyl (5-nitro-2-phenyl-1H-indol-1-yl)acetate:

¹H NMR (DMSO-d₆) 1.11 (t, J=7.02 Hz, 3H); 4.09 (q, J=7.02 Hz, 2H); 5.15(s, 2H); 6.90 (d, J=0.58 Hz, 1H); 7.46-7.60 (m, 5H); 7.73 (d, J=9.35 Hz,1H); 8.08 (dd, J=9.06, 2.34 Hz, 1H); 8.60 (d, J=2.34 Hz, 1H).

ethyl (5-amino-2-phenyl-1H-indol-1-yl)acetate:

¹H NMR (CDCl₃) 1.23 (t, J=7.16 Hz, 3H); 2.97 (br. s., 2H); 4.20 (q,J=7.02 Hz, 2H); 4.74 (s, 2H); 6.45 (s, 1H); 6.79 (dd, J=8.77, 2.05 Hz,1H); 7.06 (s, 1H); 7.08 (d, J=5.85 Hz, 1H); 7.34-7.52 (m, 5H).

i) 1-[2-(dimethylamino)ethyl]-2-phenyl-1H-indol-5-amine

The process described above in Example 1f) was used, except that2-chloro-N,N-dimethylethanamine hydrochloride was used instead of ethyl4-bromobutanoate

N,N-dimethyl-2-(5-nitro-2-phenyl-1H-indol-1-yl)ethanamine:

¹H NMR (DMSO-d₆) 1.98 (s, 6H); 2.41 (t, J=6.87 Hz, 2H); 4.36 (t, J=6.87Hz, 2H); 6.81 (s, 1H); 7.45-7.65 (m, 5H); 7.77 (d, J=9.06 Hz, 1H); 8.07(dd, J=9.06, 2.34 Hz, 1H); 8.56 (d, J=2.34 Hz, 1H).

1-[2-(dimethylamino)ethyl]-2-phenyl-1H-indol-5-amine:

¹H NMR (DMSO-d₆) 2.00 (s, 6H); 2.38 (t, J=7.31 Hz, 2H); 4.13 (t, J=7.31Hz, 2H); 4.52 (br. s., 2H); 6.23 (s, 1H); 6.57 (dd, J=8.62, 2.19 Hz,1H); 6.69 (d, J=1.75 Hz, 1H); 7.19 (d, J=8.48 Hz, 1H); 7.35-7.58 (m,5H).

l) 1-(2-methoxyethyl)-2-phenyl-1H-indol-5-amine

The process described above in Example 1f) was used, except that1-bromo-2-methoxyethane was used instead of ethyl 4-bromobutanoate

1-(2-methoxyethyl)-5-nitro-2-phenyl-1H-indole

¹H NMR (DMSO-d₆) 3.04 (s, 3H); 3.53 (t, J=5.41 Hz, 2H); 4.44 (t, J=5.41Hz, 2H); 6.83 (s, 1H); 7.46-7.66 (m, 5H); 7.79 (d, J=9.06 Hz, 1H); 8.06(dd, J=9.06, 2.34 Hz, 1H); 8.57 (d, J=2.34 Hz, 1H).

1-(2-methoxyethyl)-2-phenyl-1H-indol-5-amine

l) 4-(5-amino-2-phenyl-1H-indol-1-yl)butan-2-one

The process described above in Example 10 was used, except that4-chlorobutan-2-one was used instead of ethyl 4-bromobutanoate

4-(5-nitro-2-phenyl-1H-indol-1-yl)butan-2-one

¹H NMR (DMSO-d₆) 2.00 (s, 3H); 2.85 (t, J=7.50 Hz, 2H); 4.45 (t, J=7.50Hz, 2H); 6.83 (d, J=0.58 Hz, 1H); 7.47-7.62 (m, 5H); 7.79 (d, J=9.35 Hz,1H); 8.07 (dd, J=9.06, 2.34 Hz, 1H); 8.58 (d, J=2.34 Hz, 1H).

4-(5-amino-2-phenyl-1H-indol-1-yl)butan-2-one

¹H NMR (DMSO-d₆) 1.98 (s, 3H); 2.77 (t, J=7.68 Hz, 2H); 4.25 (t, J=7.68Hz, 2H); 4.52 (br. s., 2H); 6.24 (s, 1H); 6.57 (dd, J=8.64, 2.06 Hz,1H); 6.69 (d, J=1.92 Hz, 1H); 7.20 (d, J=8.51 Hz, 1H); 7.32-7.63 (m,5H).

m) 2-(4-fluorophenyl)-1-(2-methoxyethyl)-1H-indol-5-amine

To a solution of 5-nitroindole (3.5 g; 21.6 mmol) in DMF (100 ml) wasadded Cs₂CO₃ (13.9 g; 42.6 mmol). The mixture thus obtained was stirred1 h hour at room temperature then 1-bromo-2-methoxyethane (5.9 g; 42.6mmol) was added dropwise. The resulting mixture was heated to 120° C.under stirring for 4 hours. After cooling, the mixture was poured intowater (500 ml) and the crude product was filtered, dried under vacuum togive 1-(2-methoxyethyl)-5-nitro-1H-indole which was used in thefollowing reaction without any further purification.

¹H NMR (DMSO-d₆) 3.21 (s, 3H); 3.68 (t, J=5.26 Hz, 2H); 4.43 (t, J=5.26Hz, 2H); 6.75 (dd, J=3.22, 0.58 Hz, 1H); 7.62 (d, J=3.22 Hz, 1H); 7.70(d, J=9.35 Hz, 1H); 8.02 (dd, J=9.06, 2.34 Hz, 1H); 8.56 (d, J=2.34 Hz,1H).

To a suspension containing cesium acetate dried under vacuum overnightat 140° C. (7.3 g; 38 mmol) in N,N-dimethylacetamide (DMA, 10 ml), underan inert atmosphere, were added palladium acetate (0.22 g; 0.98 mmol),triphenylphosphine (1 g; 3.8 mmol), 1-(2-methoxyethyl)-5-nitro-1H-indole(4.2 g; 19.1 mmol) and 1-iodo-4-fluorobenzene (4.7 g; 21 mmol).

The reaction mixture was left under stirring at 140° C. under an inertatmosphere for 18 hours. The mixture was then cooled to roomtemperature, dichloromethane (100 ml) was added and the mixture thusobtained was filtered under vacuum through Celite.

The organic solution was transferred into a separating funnel, washedwith H₂O (2×100 ml) and dried over Na₂SO₄.

The organic solvent was removed by evaporation under reduced pressureand the residue was purified by flash chromatography on silica gel(n-hexane/EtOAc, n-hexane 100→60%) to give2-(4-fluorophenyl)-1-(2-methoxyethyl)-5-nitro-1H-indole (0.9 g), whichwas used without any further purification.

¹H NMR (DMSO-d₆) 3.05 (s, 3H); 3.53 (t, J=5.33 Hz, 2H); 4.41 (t, J=5.41Hz, 2H); 6.83 (s, 1H); 7.32-7.44 (m, 2H); 7.62-7.73 (m, 2H); 7.79 (d,J=9.21 Hz, 1H); 8.06 (dd, J=9.06, 2.34 Hz, 1H); 8.57 (d, J=2.34 Hz, 1H).

To a suspension containing2-(4-fluorophenyl)-1-(2-methoxyethyl)-5-nitro-1H-indole (0.9 g; 2.9mmol) in ethanol absolute (100 ml) was added stannous chloride dihydrate(3.3 g; 14.6 mmol). The reaction mixture was left under stirring at 75°C. for 48 hours. The mixture was then cooled to room temperature, thesolvent partially evaporated under reduced pressure and poured in water(100 ml) and ice. NaHCO₃ (saturated solution) was added to pH 8 and themixture was left under stirring for 20 minutes. The solution wastransferred into a separating funnel, and extracted with ethyl acetate(2×50 ml). The organic phases were combined, and the resulting organicphase was washed with H₂O (2×100 ml) and dried over Na₂SO₄.

The organic solvent was removed by evaporation under reduced pressureand the residue was purified by flash chromatography on silica gel(n-hexane/EtOAc, n-hexane 100→60%) to give2-(4-fluorophenyl)-1-(2-methoxyethyl)-1H-indol-5-amine (0.7 g), whichwas used without any further purification.

¹H NMR (DMSO-d₆) 3.07 (s, 3H); 3.51 (t, J=5.70 Hz, 2H); 4.18 (t, J=5.85Hz, 2H); 4.53 (br. s., 2H); 6.22 (s, 1H); 6.56 (dd, J=8.62, 2.19 Hz,1H); 6.69 (d, J=1.46 Hz, 1H); 7.22 (d, J=8.77 Hz, 1H); 7.30 (t, J=8.92Hz, 2H); 7.59 (dd, J=9.06, 5.55 Hz, 2H).

n) 3-(5-amino-2-phenyl-1H-indol-1-yl)propyl acetate

To a solution containing ethyl3-(5-nitro-2-phenyl-1H-indol-1-yl)propanoate (prepared as described inexample 1 g) (2.1 g; 6.2 mmol) in THF (20 ml) sodium borohydride (0.98g, 24.8 mmol) and EtOH absolute (25 ml) were added; the reaction mixturewas left under stirring at room temperature for 18 hours. Then water (5ml) and HCl 2N were added to pH 6. The solution was transferred into aseparating funnel, and extracted with ethyl acetate (2×50 ml). Theorganic phases were combined, and dried over Na₂SO₄. The solvent wasremoved by evaporation under reduced pressure and the residue waspurified by flash chromatography on silica gel (n-hexane/EtOAc, n-hexane100→70%) to give 3-(5-nitro-2-phenyl-1H-indol-1-yl)propan-1-ol (1.5 g),which was used without any further purification.

¹H NMR (CDCl₃) 1.81-1.93 (m, J=6.58, 6.58, 6.43, 6.14 Hz, 2H); 3.36 (t,J=5.70 Hz, 2H); 3.50 (br. s., 1H); 4.38 (t, J=7.02 Hz, 2H); 6.69 (s,1H); 7.28-7.61 (m, 6H); 8.06 (dd, J=9.06, 2.34 Hz, 1H); 8.55 (d, J=2.05Hz, 1H).

To a solution containing ethyl 3-(5-nitro-2-phenyl-1H-indol-1-yl)propan-1-ol (2.2 g; 7.4 mmol) and triethylamine (1.24 ml; 8.9 mmol) inCH₂Cl₂ (20 ml), acetyl chloride (0.6 ml; 8.9 mmol) was added dropwise;the reaction mixture was left under stirring at room temperature for 2hours. Then water (20 ml) and NaHCO₃ (saturated solution) were added topH 7. The biphasic solution was transferred into a separating funnelextracted with CH₂Cl₂ (2×50 ml). The organic phases were combined,washed with brine (2×100 ml) and dried over Na₂SO₄. The solvent wasremoved by evaporation under reduced pressure to give3-(5-nitro-2-phenyl-1H-indol-1-yl)propyl acetate (1.5 g), which was usedwithout any further purification.

¹H NMR (DMSO-d₆) 1.79 (s, 3H); 1.86 (qd, J=6.63, 6.43 Hz, 2H); 3.75 (t,J=5.99 Hz, 2H); 4.41 (t, J=7.16 Hz, 2H); 6.85 (s, 1H); 7.47-7.64 (m,5H); 7.79 (d, J=9.06 Hz, 1H); 8.08 (dd, J=9.06, 2.34 Hz, 1H); 8.59 (d,J=2.05 Hz, 1H).

To a suspension of 10% Pd/C (87 mg, 0.08 mmol) in 95° ethanol (100 ml) asolution of 3-(5-nitro-2-phenyl-1H-indol-1-yl)propyl acetate (2.76 g; 8mmol) in 95° ethanol (200 ml) was added and the mixture underwenthydrogenation in a Parr hydrogenator (H₂, 30 psi) for 4 hours.

The residue was filtered under vacuum through Celite to remove thecatalyst and the solvent evaporated to give crude3-(5-amino-2-phenyl-1H-indol-1-yl)propyl acetate which was used withoutany further purification.

o) 2-(5-amino-2-phenyl-1H-indol-1-yl)ethyl acetate

The process described above in Example 1n) was used, except that ethyl(5-nitro-2-phenyl-1H-indol-1-yl)acetate (prepared as described inexample 1h) was used instead of3-(5-nitro-2-phenyl-1H-indol-1-yl)propanoate.

2-(5-nitro-2-phenyl-1H-indol-1-yl)ethanol

¹H NMR (DMSO-d₆) 3.63 (t, J=5.85 Hz, 2H); 4.32 (t, J=5.85 Hz, 2H); 6.46(br. s., 1H); 6.83 (s, 1H); 7.43-7.71 (m, 5H); 7.77 (d, J=9.06 Hz, 1H);8.06 (dd, J=9.06, 2.34 Hz, 1H); 8.57 (d, J=2.34 Hz, 1H).

ethyl 2-(5-nitro-2-phenyl-1H-indol-1-yl)acetate

¹H NMR (DMSO-d₆) 1.70 (s, 3H); 4.16 (t, J=5.26 Hz, 2H); 4.57 (t, J=5.26Hz, 2H); 6.83 (s, 1H); 7.35-7.70 (m, 5H); 7.81 (d, J=9.35 Hz, 1H); 8.09(dd, J=9.35, 2.34 Hz, 1H); 8.58 (d, J=2.34 Hz, 1H).

p) 2-cyclohexyl-1-ethyl-1H-indol-5-amine

To a solution containing 2-iodo-4-nitroaniline (25 g; 95 mmol) andtriethylamine (43 ml; 312 mmol) in CH₂Cl₂ (250 ml), a solutioncontaining methanesulphonyl chloride (36 g; 312 mmol) was addeddropwise. The reaction mixture was left under stirring at roomtemperature for 18 hours, then NH₄Cl (saturated solution) was added (250ml). The biphasic solution was transferred into a separating funnel, theorganic phase was separated, dried over Na₂SO₄ and the solvent wasremoved by evaporation under reduced pressure. The residue was suspendedin EtOH (200 ml) and heated under stirring until a yellow solidprecipitated. The crude product was filtered, washed with EtOH (750 ml),and dried under vacuum to giveN-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)methanesulfonamide (32 g)which was used in the following reaction without any furtherpurification.

¹H NMR (DMSO-d₆) 3.68 (s, 6H); 7.93 (d, J=8.77 Hz, 1H); 8.29 (dd,J=8.48, 2.34 Hz, 1H); 8.73 (d, J=2.63 Hz, 1H).

To a mixture containingN-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)methanesulfonamide (31 g; 75mmol) in EtOH (230 ml), water (115 ml) and LiOH (9 g; 375 mmol) wereadded. The reaction mixture was refluxed for 2 hours, then cooled toroom temperature, the solvent evaporated under reduced pressure. NH₄Cl(saturated solution, 250 ml) was added and the mixture was stirred untila yellow solid precipitated. The crude product was filtered and driedunder vacuum to give N-(2-iodo-4-nitrophenyl)methanesulfonamide (24 g)which was used in the following reaction without any furtherpurification.

¹H NMR (DMSO-d₆) 3.01 (s, 3H); 7.41 (d, J=9.06 Hz, 1H); 8.10 (dd,J=9.21, 2.78 Hz, 1H); 8.53 (d, J=2.92 Hz, 1H); 9.55 (br. s., 0H).

To a mixture containing N-(2-iodo-4-nitrophenyl)methanesulfonamide (13.5g; 39.5 mmol), triethylamine (17.9 ml; 129 mmol), ethynylcyclohexane(8.55 g; 79 mmol) in DMF (60 ml), CuI (1.5 g; 7.9 mmol) anddichlorobis(triphenylphosphine)palladium(II) [Cl₂(PPh₃)₂Pd] (2.77 g;3.95 mmol) were added. The reaction mixture was left under stirring at70° C. for 18 hours. After cooling to room temperature, EtOAc (100 ml)was added, the inorganic precipitate was filtered off and the solutionwas transferred into a separating funnel and washed with NaHCO₃(saturated solution, 3×200 ml) and water (2×150 ml). The organic phasewas dried over Na₂SO₄, the solvent was removed by evaporation underreduced pressure. The so obtained crude product was crystallized(isopropyl ether) to give2-cyclohexyl-1-(methylsulfonyl)-5-nitro-1H-indole (11.7 g)

¹H NMR (DMSO-d₆) 1.14-1.53 (m, 5H); 1.62-1.93 (m, 3H); 2.02-2.20 (m,2H); 3.08-3.27 (m, 1H); 3.46 (s, 3H); 6.87 (s, 1H); 8.09 (d, J=9.10 Hz,1H); 8.17 (dd, J=9.10, 2.05 Hz, 1H); 8.52 (d, J=2.05 Hz, 1H).

To a solution containing2-cyclohexyl-1-(methylsulfonyl)-5-nitro-1H-indole (5.8 g; 18 mmol) inTHF (50 ml), tetrabutylammonium fluoride (1M solution in THF; 18 ml; 18mmol) was added dropwise. The reaction mixture was refluxed for 18hours, then cooled to room temperature. Water (50 ml) and EtOAc (50 ml)were added, the biphasic solution was transferred into a separatingfunnel, the organic layer separated and dried over Na₂SO₄, and thesolvent was removed by evaporation under reduced pressure. The residuewas purified by flash chromatography on silica gel (n-hexane/EtOAc,n-hexane 100→480%) to give 2-cyclohexyl-5-nitro-1H-indole (3.2 g), whichwas used without any further purification.

¹H NMR (DMSO-d₆) 1.12-1.58 (m, 5H); 1.64-1.87 (m, 3H); 1.95-2.12 (m,2H); 2.67-2.85 (m, 1H); 6.41 (d, J=1.98 Hz, 1H); 7.43 (d, J=8.92 Hz,1H); 7.92 (dd, J=8.92, 2.31 Hz, 1H); 8.43 (d, J=2.31 Hz, 1H); 11.66 (br.s., 1H).

To a solution of 2-cyclohexyl-5-nitro-1H-indole (5 g; 20.5 mmol) in DMF(100 ml) sodium hydride (50% suspension) (1 g, 20.5 mmol) was added; themixture was left under stirring for 30 minutes, then ethyl iodide (2.5ml; 30.8 mmol) in DMF (10 ml) was added dropwise and the resultingmixture was left under stirring at room temperature for 18 hours. Thereaction mixture was poured in NaHCO₃ (saturated solution, 100 ml) andstirred for 30 minutes. The solid was filtered under vacuum to give2-cyclohexyl-1-ethyl-5-nitro-1H-indole (4.8 g) which was used withoutany further purification.

¹H NMR (DMSO-d₆) 1.16-1.56 (m, 5H); 1.29 (t, J=7.09 Hz, 3H); 1.67-1.89(m, 3H); 1.90-2.05 (m, 2H); 2.69-2.86 (m, 1H); 4.28 (q, J=7.16 Hz, 2H);6.52 (s, 1H); 7.62 (d, J=9.06 Hz, 1H); 7.96 (dd, J=9.06, 2.34 Hz, 1H);8.45 (d, J=2.34 Hz, 1H).

To a suspension of 10% Pd/C (380 mg, 0.36 mmol) in 95° ethanol (50 ml) asolution of 2-cyclohexyl-1-ethyl-5-nitro-1H-indole (4.8 g; 18 mmol) in95° ethanol (100 ml) was added and the mixture underwent hydrogenationin a Parr hydrogenator (H₂, 30 psi) for 4 hours. The residue wasfiltered under vacuum through Celite to remove the catalyst and thesolvent evaporated to give crude 2-cyclohexyl-1-ethyl-1H-indol-5-amine(4 g) which was used without any further purification.

Monoisotopic mass=242.18; GC/MS (M)⁺ m/z=242.

q) 2-phenethyl-1-ethyl-1H-indol-5-amine

To a solution of 2-iodo-4-nitroaniline (1.02 g, 3.86 mmol) indichloromethane (10 ml), has been added under stirring triethylamine(1.77 ml, 12.7 mmol). To this mixture, a solution of methanesulphonylchloride (0.98 ml, 12.7 mmol) in dichloromethane (2 ml) has been addeddropwise, very slowly and in an ice-bath. The mixture so obtained wasleft under stirring at room temperature overnight. The day after, thereaction mixture was neutralized with a saturated aqueous solution ofNH₄Cl. The organic phase was separated, and, after evaporation of thesolvent, the residue has been washed with ethanol and filtered to giveN-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)-methanesulfonamide as yellowsolid.

N-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)methanesulfonamide:

¹H-NMR (DMSO-d₆): 8.73 (d, J=2.6 Hz, 1H); 8.29 (dd, J=8.8, 2.6 Hz, 1H);7.93 (d, J=8.8 Hz, 1H); 3.68 (s, 6H).

LiOH (0.21 mg, 8.9 mmol) in a mixture ethanol/water 2/1 (18 ml) wasadded to a solution ofN-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)methanesulfonamide (0.75 g,1.78 mmol). The reaction mixture was refluxed for two hours. Aftercooling at room temperature, the reaction mixture was neutralized withH₂O, NH₄Cl and HCl 2N, then ethanol was eliminated, and the aqueousphase was extracted with ethyl acetate (3×20 ml). The organic solventwas removed by evaporating under reduced pressure to giveN-(2-iodo-4-nitrophenyl)methanesulfonamide without further purification.

N-(2-iodo-4-nitrophenyl)methanesulfonamide:

¹H-NMR (DMSO-d₆): 9.53 (br. s., 1H); 8.59 (d, J=2.2 Hz, 1H); 8.19 (dd,J=8.8, 2.7, 1H); 7.55 (d, J=8.8, 1H); 3.14 (s, 3H).

CuI (0.06 g, 0.34 mmol) previously maintained in oven for at least 48hours, bis(triphenylphosphino)palladium dichloride (0.2 g, 0.17 mmol),triethylamine (1.1 ml, 7.82 mmol) and 4-phenyl-1-butyne (0.44 g, 3.4mmol) was added to a solution ofN-(2-iodo-4-nitrophenyl)methanesulfonamide (0.6 g, 1.7 mmol) inanhydrous DMF (20 ml) kept under nitrogen atmosphere. The reactionmixture was left under stirring overnight. Next morning, after cooling,the reaction mixture was poured in H₂O and ice (200 ml) leaving understirring for some hours. After filtration, a brown solid was recovered,recrystallized from ethyl acetate/hexane 1:1, and then from iPrOH/EtOH9:1. The residue was filtered to give1-(methylsulfonyl)-5-nitro-2-(2-phenethyl)-1H-indole.

1-(methylsulfonyl)-5-nitro-2-(2-phenethyl)-1H-indole:

¹H-NMR (DMSO-d₆): 8.53 (d, J=2.0 Hz, 1H); 8.18 (dd, J=8.4, 2.5, 1H);8.10 (d, 1H); 7.29 (m, 5H); 6.91 (s, 1H); 3.52 (s, 3H); 3.29 (m, 2H);3.05 (m, 2H).

Tetrabutyl ammonium fluoride (TBAF, 0.37 ml, 1.29 mmol) was added to asolution of 1-(methylsulfonyl)-5-nitro-2-(2-phenethyl)-1H-indole (0.25g, 0.95 mmol) in THF (5 ml). The reaction mixture was refluxed overnightunder stirring. The next morning, after cooling, the reaction mixturewas poured in H₂O, and kept under stirring overnight. After filtration,the solid was purified with flash chromatography on silica gel(n-hexane/EtOAc, n-hexane 90→80%) to give 2-phenethyl-5-nitro-1H-indole.

2-phenethyl-5-nitro-1H-indole:

¹H NMR (300 MHz, DMSO-d6) δ 11.76 (br. s., 1H), 8.42 (d, J=2.31 Hz, 1H),7.93 (dd, J=2.31, 8.92 Hz, 1H), 7.45 (d, J=8.92 Hz, 1H), 7.11-7.34 (m,5H), 6.45 (s, 1H), 2.97-3.15 (m, 4H)

A 60% dispersion of NaH (0.5 g, 2.02 mmol) was added to a solution of2-phenethyl-5-nitro-1H-indole (0.16 g, 0.6 mmol) in DMF (30 ml). Thereaction mixture was kept under stirring for 30 minutes. Then, ethyliodide (0.15 ml, 1.9 mmol) was added, and the mixture was left understirring overnight at room temperature. The next morning, the mixturewas poured in H₂O left under stirring overnight, obtaining a precipitatewhich was filtered to give 2-phenethyl-1-ethyl-5-nitro-1H-indole.

2-phenethyl-1-ethyl-5-nitro-1H-indole:

¹H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=2.05 Hz, 1H), 7.97 (dd, J=2.34,9.06 Hz, 1H), 7.62 (d, J=9.06 Hz, 1H), 7.13-7.40 (m, 5H), 6.58 (s, 1H),4.26 (q, J=7.31 Hz, 2H), 2.99-3.18 (m, 4H), 1.25 (t, J=7.20 Hz, 3H)

SnCl₂ (1.2 g, 6.3 mmol) was added to a solution of2-phenethyl-1-ethyl-5-nitro-1H-indole (0.17 g, 0.57 mmol) in THF (50ml). The mixture was kept under stirring at 70° C. overnight. Aftercooling, the mixture was poured in H₂O, neutralized with NaHCO₃, andextracted with ethyl acetate (3×50 ml). After evaporation of the solventunder reduced pressure, the solid was purified on a chromatographiccolumn using CHCl₃ as eluent to give2-phenethyl-1-ethyl-1H-indol-5-amine.

2-phenethyl-1-ethyl-1H-indol-5-amine:

¹H NMR (300 MHz, DMSO-d₆) δ 7.25-7.37 (m, 4H), 7.15-7.25 (m, 1H), 7.11(d, J=8.48 Hz, 1H), 6.72 (d, J=2.05 Hz, 1H), 6.53 (dd, J=2.19, 8.62 Hz,1H), 6.02 (s, 1H), 5.46 (br. s., 2H), 4.05 (q, J=7.11 Hz, 2H), 2.81-3.15(m, 4H), 1.18 (t, J=7.16 Hz, 3H)

r) 2-benzyl-1-ethyl-1H-indol-5-ammina

The intermediate compound r) was prepared with a procedure similar tothat described for the intermediate compound q) by using3-phenyl-1-propyne (0.16 g, 1.4 mmol) instead of 4-phenyl-1-butyne.

2-benzyl-1-(methanesulfonyl)-5-nitro-1H-indole:

¹H-NMR (DMSO-d₆): 8.54 (d, J=2.3 Hz, 1H); 8.17 (m, 1H); 8.08 (m, 1H);7.35 (m, 5H); 6.53 (s, 1H); 4.37 (s, 2H); 3.37 (s, 3H).

2-benzyl-5-nitro-1H-indole:

¹H-NMR (DMSO-d₆): 11.74 (bs, 1H); 8.44 (d, J=2.3 Hz, 2H); 7.92 (dd,J=8.9, 2.3 Hz, 1H); 7.44 (d, J=8.9, 1H); 7.32 (m, 4H); 7.24 (m, 1H);6.44 (s, 1H); 4.12 (s, 2H).

2-benzyl-1-ethyl-5-nitro-1H-indole:

¹H-NMR (DMSO-d₆): 8.48 (d, J=2.3 Hz, 1H); 7.98 (dd, J=9.1, 2.3 Hz, 1H);7.60 (d, J=9.1 Hz, 1H); 7.30 (m, 5H); 6.43 (s, 1H); 4.22 (m, 4H); 1.09(t, J=7.2 Hz, 3H).

2-benzyl-1-ethyl-1H-indol-5-amine:

¹H-NMR (DMSO-d₆): 7.22 (m, 5H); 7.04 (d, J=8.5 Hz, 1H); 6.84 (d, J=2.3Hz, 1H); 6.59 (dd, J=8.5, 2.3 Hz, 1H); 6.05 (s, 1H); 4.05 (s, 2H); 3.94(q, J=7.2 Hz, 2H); 3.22 (bs, 2H); 1.10 (t, J=7.2 Hz, 3H).

s) 5-amino-1-(3-triisopropylsilanyloxypropyl)-1H-indol-2-carboxylic acidphenylamide

N₂H₄*H₂O (25 ml) was added dropwise to a solution of1-fluoro-4-nitrobenzene. The mixture was kept under stirring, at firstat room temperature for 3 hours, and then under reflux for 1 hour. Aftercooling, the resulting precipitate was filtered and washed with H₂O togive 4-nitrophenylhydrazine which was used in the next reaction withoutany further purification.

4-nitrophenylhydrazine: M/z (APCI⁺) 154 (MH⁺)

A suspension in water (150 ml) of 4-nitrophenylhydrazine (15 g, 23 mmol)and 2-oxo-propionic acid ethyl ester (12 g, 100 mmol) was left understirring at room temperature for 6 hours. The obtained precipitate wasfiltered and washed to give the ethyl ester of the2-[(4-nitrophenyl)-hydrazono]-propionic acid.

¹H-NMR (DMSO-d₆): 10.45 (s, 1H); 8.21-8.15 (m, 2H); 7.42-7.36 (m, 2H);4.28-4.15 (m, 2H); 2.15 (s, 3H); 1.36-1.22 (m, 3H).

Polyphosphoric acid (PPA, 50 g) was added to a solution of ethyl esterof the 2-[(4-nitrophenyl)-hydrazono]-propionic acid (6 g, 23 mmol) intoluene (70 ml). The mixture was refluxed for 3 hours, then was cooledat 0-10° C., and added with NH₄Cl until pH 8-9. The mixture wasextracted with ethyl acetate (EtOAc), and then the solvent was removedby evaporation under reduced pressure. The residue was purified by flashchromatography on silica gel (n-hexane/EtOAc, 80/20) and crystallizedwith CH₂Cl₂ to give the ethyl ester of 5-nitro-1H-indole-2-carboxylicacid.

Ethyl ester of 5-nitro-1H-indole-2-carboxylic acid:

¹H-NMR (DMSO-d₆): 12.55 (s, 1H); 8.73 (s, 1H); 8.14 (d, 1H); 7.62 (d,1H); 7.45 (s, 1H); 4.45-4.32 (m, 2H); 1.43-1.30 (m, 3H).

Anhydrous K₂CO₃ (2.36 g, 17.1 mmol), 18-crown-6 (1.14 g, 4.28 mmol) and3-triisopropylsilanyloxypropyl bromide (3.78 g, 12.82 mmol) were addedto a solution of ethyl ester of 5-nitro-1H-indole-2-carboxylic acid (2g, 8.85 mmol) in anhydrous acetonitrile (50 ml). The mixture was heatedat 80° C. for 4 hours. After evaporation of the solvent under reducedpressure, water was added, and the resulting mixture was extracted withdichloromethane. After evaporation of the solvent under reducedpressure, the solid was purified by flash chromatography on silica gel(n-hexane/EtOAc, 50/10) to give the ethyl ester of5-nitro-1-(triisopropylsilaniloxypropyl)-1H-indole-2-carboxylic acid:M/z (APCI⁺) 449 (MH⁺)

The ethyl ester of5-nitro-1-(triisopropylsilaniloxypropyl)-1H-indole-2-carboxylic acid(2.76 g, 6.2 mmol) was dissolved in a solution of KOH 5% in EtOH/H₂O 1/1(80 ml) and left under stirring at room temperature for 16 hours.Ethanol was then evaporated, and 1N HCl was added to the solution untilto pH 5. The solution was then extracted with EtOAc. After evaporationof the solvent under reduced pressure, the solid was washed withn-hexane/dichloromethane 10/1 and filtered to give the5-nitro-1-(triisopropylsilaniloxypropyl)-1H-indole-2-carboxylic acid.

5-nitro-1-(triisopropylsilaniloxypropyl)-1H-indole-2-carboxylic acid:

M/z (APCI⁺) 421 (MH⁺)

A mixture of 5-nitro-1-(triisopropylsilaniloxypropyl)-1H-indole-2-carboxylic acid (0.448 g, 1.065mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU) (0.478 g, 1.49 mmol) and triethylamine (0.22ml, 1.59 mmol) in anhydrous acrylonitrile (14 ml) was kept understirring at room temperature for 30 minutes. Aniline (0.109 g, 1.175mmol) was added to this mixture. The mixture was left at 50°-55° C. forabout 3 hours, and then diluted with H₂O and extracted with ethylacetate (EtOAc). After evaporation of the solvent under reducedpressure, the obtained solid was purified by flash chromatography onsilica gel (n-hexane/EtOAc, 50/10) to give phenylamide of5-nitro-1-(triisopropylsilaniloxypropyl)-1H-indole-2-carboxylic acid:

M/z (APCI⁺) 496 (MH⁺)

A catalytic amount of 10% Pd/C was added to a solution of phenylamide of5-nitro-1-(triisopropylsilaniloxypropyl)-1H-indole-2-carboxylic acid(0.323 g, 0.65 mmol) in MeOH (100 ml), and the mixture was hydrogenatedat 29 psi for 12 hours. The solution was filtered through Celite™ andthe filtrate was evaporated under reduced pressure to give a solid usedwithout any further purification.

Phenylamide of5-amino-1-(triisopropylsilaniloxypropyl)-1H-indole-2-carboxylic acid:M/z (APCI⁺) 466 (MH⁺).

EXAMPLE 2 Preparation of Compounds of the Invention

a) Example of a first variant of the preparation process:

To a solution of a 5-amino(aza)indole (III) (2 mmol) in dichloromethane(10 ml) was added triethylamine (2.2 mmol), followed by dropwiseaddition of an acyl chloride (II) (2.2 mmol) dissolved indichloromethane (10 ml). Once the additions were complete, the mixturewas left under stirring at room temperature for 20 hours. Water (50 ml)was then added and the organic phase was separated out and dried overNa₂SO₄. The solution was evaporated under reduced pressure. The crudeproduct obtained was purified to give compound of formula (I) in whichX, Y, Z, G1, G2, G3, R1, W and R2 have the meanings given above.

b) Example of a second variant of the preparation process:

To a suspension of 5-amino(aza)indole (III) (0.9 mmol) were addedAmberlyst A21 resin (0.9 g) in dichloromethane (3 ml) and an acylchloride (II) (0.28 mmol) in dichloromethane (3 ml). The mixture wasleft under stirring for 20 hours. The Amberlyst A21 resin was thenremoved by filtration and washed with dichloromethane (5 ml). Theorganic phases were combined, diluted with dimethylformamide (1 ml) andstirred with Amberlyst 15 resin (0.9 g) for 5 hours. This treatment wasrepeated twice. The Amberlyst 15 resin was removed by filtration and thesolution was evaporated under centrifuge to give compound of formula (I)in which X, Y, Z, G1, G2, G3, R1, W and R2 have the meanings givenabove.

c) Example of a third variant of the preparation process:

Under an inert atmosphere, a benzoic acid (II) (0.67 mmol) and a5-amino(aza)indole (III) (0.45 mmol) were dissolved in dichloromethane(8 ml) and dimethylformamide (0.8 ml). After leaving the mixturestirring at room temperature for 10 minutes, PS-carbodiimide resin (0.73g) was added.

After leaving the reaction mixture stirring for 20 hours, the resin wasremoved by filtration and washed with dichloromethane (2×5 ml). Thesolution was evaporated under centrifugation to give compound of formula(I) in which X, Y, Z, G1, G2, G3, R1, W and R2 have the meanings givenabove.

d) Example of a fourth variant of the preparation process:

To a solution of a benzoic acid (II) (10 mmol) in dimethylformamide (40ml) with stirring at 0° C., 1-hydroxybenzotriazol (HOBt) (10 mmol) anddicyclohexylcarbodiimide (DCC) (10 mmol) were added. The mixture wasleft under stirring at 0° C. for 30 minutes and a 5-amino(aza)indole(III) (9 mmol) dissolved in dimethylformamide (20 ml) was added.

The mixture was left under stirring at 0° C. for a further 30 minutes,and then at room temperature for 18 hours. The mixture was filtered, 2Nhydrochloric acid was added to pH 2, and the precipitate thus formed wasfiltered off and purified to give compound of formula (I) in which X, Y,Z, G1, G2, G3, R1, W and R2 have the meanings given above.

e) Example of a fifth variant of the preparation process:

To a suspension of cesium acetate dried under vacuum overnight at 140°C. (6.02 mmol) in N,N-dimethylacetamide (DMA) (3 ml), under an inertatmosphere, were added palladium acetate (0.017 mmol),triphenylphosphine (0.067 mmol), 5-amino(aza)indole (IV)^(I) (3.35 mmol)and an aryl iodide (V) (3.68 mmol).

The reaction mixture was left under stirring at 140° C. under an inertatmosphere for 18 hours. The reaction mixture was cooled to roomtemperature, dichloromethane (50 ml) was added and the resulting mixturewas filtered under vacuum through Celite. The filtered organic solutionwas transferred into a separating funnel. The organic phase was washedwith H₂O (2×50 ml), dried over Na₂SO₄ and evaporated under reducedpressure.

The residue was purified to give compound of formula (I) in which X, Y,Z, G1, G2, G3, R1, W and R2 have the meanings given above.

f) Example of solid phase preparation using a PL-FMP resin:

The following example of solid phase preparation by using a preparativeresin is given with specific reference to compounds of the presentinvention wherein the above mentioned G1, G2, G3 groups are CH and R1 isSO2R^(I) and X, Y, Z, W, R2 and R^(I) have the meanings given above.Additionally, the following example comprises steps 1 and 2 to preparethe starting compound B1 of the process of the present invention becauseintermediate A1 is first prepared in situ without separation from thepreparative resin.

Step (1): 15 g of PL-FMP resin (0.9 mmol/g) in a solution 1% AcOH in DMF(300 ml) was stirred at room temperature for 2 h. Then,N-(4-amino-2-iodophenyl)alkylsulfonamide (54 mmol) and 11.5 g of sodiumtriacetoxyborohydride (54 mmol) were added. PL-FMP Resin (manufacturedby Polymer Laboratories, UK) is an aldehyde-based resin suitable forattachment of amines via reductive amination. The mixture was stirred atroom temperature for 24 h, then the resin was filtered and washed withDMF (3×150 ml), DMF/MeOH in a 1/1 volume ratio (3×150 ml), MeOH (3×150ml), CH₂Cl₂/MeOH in a 1/1 volume ratio (3×100 ml), and CH₂Cl₂ (3×100ml). The resin was dried under vacuum at room temperature to give 18.3 gof resin (A1) which was used without any further purification.

Step (2): 1.172 g of resin (A1) (0.8 mmol, theoretical) were added to amixture of DMF (10 ml), the B2 alkyne (5 mmol), CuI (32 mg, 0.17 mmol),58 mg of dichlorobis(triphenylphosphine)palladium(11) [Cl₂(PPh₃)₂Pd](0.8 mmol) and 2 ml of triethylamine (22 mmol). The mixture was heatedat 70° C. and stirred for 48 h.

The reaction was quenched by cooling to room temperature. The resin wasfiltered and washed with DMF (3×10 ml), DMF/H₂O in a 95/5 volume ratio(3×10 ml), DMF/H₂O in a 90/10 volume ratio (3×10 ml), DMF/H₂O in a 80/20volume ratio (3×10 ml), DMF/H₂O in a 50/50 volume ratio (3×10 ml), DMF(3×10 ml), DMF/MeOH in a 50/50 volume ratio (3×10 ml), MeOH (3×10 ml),MeOH/CH₂Cl₂ in a 50/50 volume ratio (3×10 ml), and CH₂Cl₂ (3×10 ml). Theresin B1 so far obtained, was used without any further purification.

Step (3): 1.38 ml of N,N-diisopropylethylamine (DIEA, 8.0 mmol) and acylchloride (6.5 mmol) (C2) were added to a suspension of resin (B1) inCH₂Cl₂ (10 ml). The mixture was stirred at room temperature for 18 h,then the resin was filtered and washed with CH₂Cl₂ (3×10 ml), CH₂Cl₂/DMFin a 1/1 volume ratio (3×10 ml), DMF (3×10 ml), DMF/H₂O in a 9/1 volumeratio (3×10 ml), DMF (3×10 ml), DMF/MeOH in a 1/1 volume ratio (3×10ml), MeOH (3×10 ml), CH₂Cl₂/MeOH in a 1/1 volume ratio (3×10 ml), CH₂Cl₂(3×10 ml). The resin (C1) so far obtained, was used without any furtherpurification.

Step (4): The resin (C1) was added to a solution of triethylsilane (0.15ml) in TFA/DCM in a 1/1 volume ratio (15 ml) and stirred at roomtemperature for 15 minute. The resin was filtered and washed withsolution of triethylsilane (0.15 ml) in TFA/DCM in a 1/1 volume ratio (5ml). The solution was evaporated under vacuum to give the crude productthat was purified with preparative HPLC to give compound (I) in which X,Y, Z, W, R2 and R^(I) have the meanings given above.

g) Example of reduction of double bond in position 2-3:

A 5-amino(aza)indole derivative (1 mmol) was dissolved in a solution ofEtOH (3 ml) and HCl conc. (1.5 ml). Then, tin (5 mmol) was added and themixture was refluxed for 6 hours. The mixture was filtered, the solutionpoured in a 20% KOH solution (5 ml), and extracted with Et₂O (3×10 ml).Organic phase was filtered on Celite and dried over Na₂SO₄. The solutionwas evaporated under reduced pressure. The crude product obtained waspurified to give compound of formula (I′) in which X, Y, Z, G1, G2, G3,R1, W and R2 have the meanings given above.

h) Example of preparation of acid from the corresponding ester:

An (aza)indolester derivative (0.32 mmol) was dissolved in a solution ofTHF/EtOH in a 1/1 volume ratio (3 ml), then a solution of NaOH 1N wasadded (1.2 ml) and the mixture was stirred a room temperature for 3 h.

The organic solvents were removed under vacuum and 1N HCl solution wasadded until precipitation of acid. The product was filtered, washed withwater and dried under vacuum to give compound of formula (I) in which X,Y, Z, G1, G2, G3, n, W and R2 have the meanings given above.

i) Example of a sixth variant of the preparation process:

In inert atmosphere, a benzoic acid (II) (0.74 mmol), TBTU (0.86 mmol)and triethylamine (0.98 mmol) have been dissolved in anhydrousacetonitrile (3 ml). After having left the mixture under stirring atroom temperature for 30 minutes, a solution of the compound (V) (0.61mmol) in anhydrous acetonitrile (3 ml) has been added. The mixture hasbeen left under stirring at room temperature for 3 hours, then dilutedwith H₂O and extracted with ethyl acetate (EtOAc). After evaporation ofthe solvent under reduced pressure, the resulting solid (0.16 mmol) hasbeen dissolved in MeOH (15 ml). To the solution. HCl 2N (2.5 ml) hasbeen added, and the mixture has been left at room temperature for 3hours. The solvent has been then evaporated under reduced pressure, andthe residue dissolved in DCM and washed with a saturated solution ofNaHCO₃. After evaporation of the organic solvent, the residue has beenpurified to give the compound (I) where Y, Z, G1, G2, and G3 have themeanings indicated above, W is an amidic bond, and R2 is a phenyl group.

The compounds of the present invention shown in Table 1 below were thusprepared. In Table 1 the following abbreviations with the followingmeanings are used:

-   -   Purification A=Crystallization    -   Purification B=Flash chromatography on silica gel    -   Purification C=Preparative HPLC (X Bridge prep. C18; 5 μm,        30×150 mm)    -   EtOAc=Ethyl acetate    -   Hex=Hexane    -   MeOH=Methanol    -   EtOH=Ethanol    -   CH₃CN=Acetonitrile    -   H₂O=Water    -   HCOOH=Formic acid    -   iPrOH=Isopropanol    -   Pr₂O=Propyl ether

TABLE 1 Ex- Monoisotopic LC/MS Compound Structural Formula amplePurification Mass (M + H)⁺ ¹H NMR (300 MHz) 1

2(a) B (Hex/EtOAc; hex 90→40%) 389.13 390.3 ¹H-NMR (CDCl₃): 8.41 (d, J =2.4 Hz, 1H); 8.32 (d, J = 2.4 Hz, 1H); 8.19 (s, 1H); 7.74 (m, 1H);7.50-7.20 (om, 7H); 6.42 (s, 1H); 4.34 (q, J = 7.2 Hz, 2H); 2.42 (s,3H); 1.27 (t, J = 7.2 Hz, 3H). 2

2(a) B (Hex/EtOAc = 8/2) 403.15 404.4 ¹H-NMR (CDCl₃): 8.405 (d, J = 2.4Hz, 1H); 8.30 (d, J = 2.4 Hz, 1H); 8.00 (s, 1H); 7.83 (m, 1H); 7.50-7.20(om, 7H); 6.37 (s, 1H); 4.67 (ept. J = 6.9 Hz, 1H); 2.43 (s, 3H); 1.69(d, J = 6.9 Hz, 6H). 3

2(a) B (Hex/EtOAc = 6/4) 419.14 420.4 ¹H-NMR (CDCl₃): 8.45 (d, J = 2.1Hz, 1H); 8.34 (d, J = 2.1 Hz, 1H); 8.13 (bs, 1H); 7.79 (m, 1H);7.55-7.20 (om, 7H); 6.46 (s, 1H); 4.49 (t, J = 6.0 Hz, 2H); 3.68 (t, J =6.0 Hz, 2H); 3.17 (s, 3H); 2.42 (s, 3H). 4

2(a) B (Hex/EtOAc = 6/4 393.10 394.3 ¹H-NMR (CDCl₃): 8.47 (d, J =2.4 Hz,1H); 8.33 (d, J = 2.4 Hz, 1H); 8.07 (s, 1H); 7.78 (m, 1H); 7.60-7.10 (2m, 7H), 6.45 (s, 1H); 4.34 (q, J = 6.9 Hz, 2H); 1.28 (t, J = 6.9 Hz 3H)5

2(a) B (Hex/EtOAc; hex 70→60%) 423.11 424.2 ¹H-NMR (CDCl₃): 8.44 (d, J =2.1 Hz); 8.33 (d, J = 2.1 Hz); 8.10 (bs, 1H), 7.78 (m, 1H), 7.65-7.10 (3m, 7H); 6.46 (s, 1H); ); 4.44 (t, J = 5.7 Hz, 2H); 3.72 (t, J = 5.7 Hz,2H); ); 3.18 (s, 3H); 6

2(a) B (Hex/EtOAc = 6/4) 422.12 423.3 1H NMR (300 MHz, DMSO-d₆) 3.07 (s,3H) 3.54 (t, J = 5.61 Hz, 2H) 4.31 (t, J = 5.45 Hz, 2H) 6.52 (s, 1H)7.29-7.69 (m, 10H) 8.03 (d, J = 1.65 Hz, 1H) 10.32 (s, 1H) 7

2(a) B (Hex/EtOAc 100→70%) 460.13 461.7 1H NMR (300 MHz, DMSO-d₆) 1.10(t, J = 7.27 Hz, 3H) 1.80 (quin, J = 7.10 Hz, 2H) 2.09 (t, J = 7.10 Hz,2H) 3.93 (q, J = 7.27 Hz, 2H) 4.25 (t, J = 7.10 Hz, 2H) 6.54 (s, 1H)7.38-7.65 (m, 11H) 8.06 (d, J = 1.98 Hz, 1H) 10.33 (s, 1H) 8

2(a) B (Hex/EtOAc; hex 100→60%) 446.14 447.7 1H NMR (300 MHz, DMSO-d₆)1.05 (t, J = 7.27 Hz, 3H) 2.59 (t, J = 7.27 Hz, 2H) 3.90 (q, J = 7.27Hz, 2H) 4.48 (t, J = 7.27 Hz, 2H) 6.54 (s, 1H) 7.38-7.66 (m, 11H) 8.04(d, J = 1.98 Hz, 1H) 10.33 (s, 1H) 9

2(a) A (Hex/EtOAc = 8/2) 417.16 418.7 1H NMR (300 MHz, DMSO-d₆) 2.00 (s,6H) 2.41 (t, J = 7.10 Hz, 2H) 4.26 (t, J = 7.10 Hz, 2H) 6.52 (s, 1H)7.38-7.63 (m, 11H) 8.04 (d, J = 1.65 Hz, 1H) 10.32 (s, 1H) 10

2(a) A (Hex/EtOAc = 8/2) 380.17 381.6 1H NMR (300 MHz, DMSO-d₆)1.17-1.57 (m, 6H) 1.25 (t, J = 7.10 Hz, 3H) 1.61-1.87 (m, 2H) 1.88-2.06(m, 2H) 2.61-2.83 (m, 1H) 4.16 (q, J = 6.94 Hz, 2H) 6.17 (s, 1H)7.26-7.38 (m, 2H) 7.39-7.62 (m, 4H) 7.88 (s, 1H) 10.21 (s, 1H) 11

2(a) B (Hex/EtOAc; hex 100→70%) 432.12 433.8 1H NMR (300 MHz, DMSO-d₆)1.13 (t, J = 7.10 Hz, 3H) 4.09 (q, J = 6.94 Hz, 2H) 5.00 (s, 2H) 6.61(s, 1H) 7.35- 7.64 (m, 11H) 8.06 (s, 1H) 10.35 (s, 1H) 12

2(a) B (Hex/EtOAc = 9/1) 404.13 405.6 1H NMR (300 MHz, DMSO-d₆) 3.06 (s,3H) 3.54 (t, J = 5.61 Hz, 2H) 4.34 (t, J = 5.78 Hz, 2H) 6.53 (s, 1H)7.35-7.68 (m, 11H) 8.03 (d, J = 1.98 Hz, 1H) 10.32 (s, 1H) 13

2(a) A (Hex/EtOAc = 8/2) 446.14 447.2 1H NMR (300 MHz, DMSO-d₆)1.76-1.93 (m, 2H) 1.80 (s, 3H) 3.72 (t, J = 5.94 Hz, 2H) 4.32 (t, J =6.94 Hz, 2H) 6.54 (s, 1H) 7.38-7.64 (m, 11H) 8.05 (d, J = 1.65 Hz, 1H)10.33 (s, 1H) 14

2(a) A (Hex/EtOAc = 8/2) 432.12 433.4 1H NMR (300 MHz, DMSO-d₆) 1.73 (s,3H) 4.15 (t, J = 5.28 Hz, 2H) 4.47 (t, J = 5.28 Hz, 2H) 6.54 (s, 1H)7.37-7.66 (m, 11H) 8.05 (d, J = 1.65 Hz, 1H) 10.34 (s, 1H) 15

2(a) B (Hex/EtOAc 7/3 416.13 417.3 1H NMR (300 MHz, DMSO-d₆) 1.99 (s,3H) 2.82 (t, J = 7.43 Hz, 2H) 4.37 (t, J = 7.43 Hz, 2H) 6.54 (s, 1H)7.24-7.74 (m, 11H) 8.05 (d, J = 1.32 Hz, 1H) 10.33 (s, 1H) 16

2(f) C (CH₃CN/H2O + 0.1% HCOOH 30→65%, 15 minutes) 438.08 439.5 1H NMR(300 MHz, DMSO-d₆) 2.37 (s, 3H) 3.01 (s, 3H) 6.87 (s, 1H) 7.24 (d, J =7.60 Hz, 2H) 7.39-7.65 (m, 7H) 7.92 (d, J = 8.92 Hz, 1H) 8.18 (d, J =1.65 Hz, 1H) 10.60 (s, 1H) 17

2(f) C (CH₃CN/H2O + 0.1% HCOOH 30→65%, 15 minutes) 424.06 425.2 1H NMR(300 MHz, DMSO-d₆) 3.04 (s, 3H) 6.92 (s, 1H) 7.39-7.64 (m, 10H) 7.92 (d,J = 9.08 Hz, 1H) 8.19 (d, J = 1.98 Hz, 1H) 10.60 (s, 1H) 18

2(f) C (CH₃CN/H2O + 0.1% HCOOH 30→65%, 15 minutes) 430.11 431.4 1H NMR(300 MHz, DMSO-d₆) 1.16-1.51 (m, 5H) 1.60- 1.90 (m, 3H) 2.10 (d, J =7.76 Hz, 2H) 3.04-3.19 (m, 1H) 3.21 (s, 3H) 6.66 (s, 1H) 7.42-7.61 (m,5H) 7.83 (d, J = 9.25 Hz, 1H) 8.04 (d, J = 1.98 Hz, 1H) 10.51 (s, 1H) 19

2(f) C (CH₃CN/H2O + 0.1% HCOOH 30→65%, 15 minutes) 425.06 426.4 1H NMR(300 MHz, DMSO-d₆) 3.79 (s, 3H) 7.10 (s, 1H) 7.35-7.66 (m, 6H) 7.76 (d,J = 7.76 Hz, 1H) 7.86-8.04 (m, 2H) 8.22 (d, J = 1.82 Hz, 1H) 8.69 (ddd,J = 4.87, 1.73, 0.83 Hz, 1H) 10.59 (s, 1H) 20

2(f) C (CH₃CN/H2O + 0.1% HCOOH 30→65%, 15 minutes) 449.06 450.3 1H NMR(300 MHz, DMSO-d₆) 3.08 (s, 3H) 7.10 (s, 1H) 7.36-7.69 (m, 5H) 7.74-7.82(m, 2H) 7.86-7.97 (m, 3H) 8.23 (d, J = 1.98 Hz, 1H) 10.64 (s, 1H) 21

2(f) C (CH₃CN/H2O + 0.1% HCOOH 30→65%, 15 minutes) 452.10 453.4 1H NMR(300 MHz, DMSO-d₆) 2.95-3.10 (m, 2H) 3.22 (t, J = 7.76 Hz, 2H) 3.27 (s,3H) 6.69 (s, 1H) 7.16-7.26 (m, J = 8.48, 4.38, 4.22, 4.22 Hz, 1H) 7.31(d, J = 4.46 Hz, 4H) 7.40-7.64 (m, 5H) 7.84 (d, J = 8.92 Hz, 1H) 8.05(t, J = 1.57 Hz, 1H) 10.52 (s, 1H) 22

2(f) C (CH₃CN/H2O + 0.1% HCOOH 30→65%, 15 minutes) 492.05 493.4 1H NMR(300 MHz, DMSO-d₆) 3.06 (s, 3H) 7.09 (s, 1H) 7.40-7.73 (m, 6H) 7.75-7.82(m, 1H) 7.85-8.00 (m, 3H) 8.22 (d, J = 1.65 Hz, 1H) 10.63 (s, 1H) 23

2(f) C (CH₃CN/H2O + 0.1% HCOOH 30→65%, 15 minutes) 458.03 459.5 1H NMR(300 MHz, DMSO-d₆) 3.05 (s, 3H) 6.97 (s, 1H) 7.40-7.70 (m, 9H) 7.92 (d,J = 9.08 Hz, 1H) 8.20 (d, J = 1.82 Hz, 1H) 10.62 (s, 1H) 24

2(f) C (CH₃CN/H2O + 0.1% HCOOH 30→65%, 15 minutes) 463.08 464.4 1H NMR(300 MHz, DMSO-d₆) 3.05 (s, 3H) 4.12 (s, 2H) 6.94 (s, 1H) 7.33-7.72 (m,9H) 7.92 (d, J = 8.92 Hz, 1H) 8.19 (d, J = 1.65 Hz, 1H) 10.61 (s, 1H) 25

2(f) C (CH₃CN/H2O + 0.1% HCOOH 30→65%, 15 minutes) 466.11 467.4 1H NMR(300 MHz, DMSO-d₆) 2.12 (s, 3H) 2.22 (s, 3H) 2.24 (s, 3H) 3.04 (s, 3H)6.73 (s, 1H) 7.04 (s, 1H) 7.17 (s, 1H) 7.42-7.65 (m, 5H) 7.91 (d, J =9.08 Hz, 1H) 8.16 (d, J = 1.98 Hz, 1H) 10.58 (s, 1H) 26

2(f) C (CH₃CN/H2O + 0.1% HCOOH 30→65%, 15 minutes) 468.09 469.4 1H NMR(300 MHz, DMSO-d₆) 2.18 (s, 3H) 3.04 (s, 3H) 3.80 (s, 3H) 6.75 (s, 1H)6.81 (dd, J = 8.26, 2.48 Hz, 1H) 6.87 (d, J = 2.64 Hz, 1H) 7.32 (d, J =8.42 Hz, 1H) 7.41- 7.66 (m, 5H) 7.91 (d, J = 8.92 Hz, 1H) 8.16 (d, J =1.82 Hz, 1H) 10.58 (s, 1H) 27

2(g) B (Hex/EtOAc = 8/2) 390.15 391.6 1H NMR (300 MHz, DMSO-d₆) 0.93 (t,J = 7.10 Hz, 3H) 2.32 (s, 3H) 2.69-2.89 (m, 2H) 3.13-3.40 (m, 2H) 4.61(dd, J = 10.24, 9.25 Hz, 1H) 6.48 (d, J = 8.26 Hz, 1H) 7.05-7.61 (m,10H) 10.11 (s, 1H) 28

2(h) A (EtOH/H₂O = 2:8) 432.12 433.5 1H NMR (300 MHz, DMSO-d₆) 1.79 (qd,J = 7.20, 7.06 Hz, 2H) 2.04 (t, J = 7.20 Hz, 2H) 4.22 (t, J = 7.27 Hz,2H) 6.54 (s, 1H) 7.34-7.69 (m, 11H) 8.06 (d, J = 1.61 Hz, 1H) 10.33 (s,1H) 12.28 (br.s., 1H) 29

2(h) A (EtOH/H₂O = 2:8) 418.11 419.8 1H NMR (300 MHz, DMSO-d₆) 2.54 (t,J = 7.90 Hz, 2H) 4.42 (t, J = 7.90 Hz, 2H) 6.54 (s, 1H) 7.37-7.64 (m,11H) 8.04 (d, J = 1.83 Hz, 1H) 10.33 (s, 1H) 12.31 (br.s., 1H) 30

2(h) A (EtOH/H₂O = 2:8) 404.09 405.6 1H NMR (300 MHz, DMSO-d₆) 4.89 (s,2H) 6.60 (s, 1H) 7.34-7.65 (m, 11H) 8.05 (s, 1H) 10.34 (s, 1H) 13.00(br.s., 1H) 31

2(a) A (EtOAc/EtOH= 5:1) 417.12 418.2 ¹H NMR (300 MHz, DMSO-d₆)2.35-2.46 (m, 2H) 4.31- 4.44 (m, 2H) 6.54 (s, 1H) 6.84 (br.s., 1H) 7.33(br.s., 1H) 7.37-7.68 (m, 11H) 8.04 (d, J = 1.98 Hz, 1H) 10.32 (s, 1H)32

2(a) A (EtOAc) 445.16 446.3 ¹H NMR (300 MHz, DMSO-d₆) 2.63 (t, J = 7.60Hz, 2H) 2.72 (s, 3H); 2.73 (s, 3H); 4.40 (t, J = 7.89 Hz, 2H); 6.54 (s,1H); 7.35-7.66 (m, 11H); 8.05 (d, J = 1.75 Hz, 1H); 10.33 (s, 1H). 33

2(a) A (Es/AcOEt) 402.92 403.3 ¹H NMR (300 MHz, DMSO-d₆) δ 10.22 (s,1H), 7.90 (s, 1H), 7.53-7.61 (m, 2H), 7.40-7.53 (m, 2H), 7.26-7.39 (m,6H), 7.15-7.26 (m, 1H), 6.26 (s, 1H), 4.14 (q, J = 7.02 Hz, 2H), 3.04(s, 4H), 1.22 (t, J = 7.02 Hz, 3H) 34

2(a) A (iPrOH/AcOEt/Pr₂O) 388.89 389.0 ¹H-NMR (DMSO-d₆): 10.23 (s, 1H);7.89 (s, 1H); 7.49 (m, 4H); 7.26 (m, 7H); 6.17 (s, 1H); 4.15 (s, 2H);4.09 (q, J = 6.9 Hz, 2H); 1.04 (t, J = 7.1 Hz, 3H). 35

2(i) B (Es/AcOEt; Es 90→66%) 482.45 482.3 ¹H-NMR (DMSO-d₆): 10.41 (bs,1H); 10.21 (bs, 1H); 8.09 (s, 1H); 7.85 (d, J = 8.5 Hz, 1H); 7.82 (m,3H); 7.71 (m, 2H); 7.59 (d, J = 8.5 Hz, 1H); 7.49 (d, J = 8.5 Hz, 1H);7.25 (t, J = 8.5 Hz, 2H); 7.31 (s, 1H); 7.11 (t, J = 8.5 Hz, 1H); 4.61(t, J = 7.5 Hz, 2H); 4.47 (t, J = 5.0 Hz, 1H); 3.41 (d, J = 7.5 Hz, 2H);1.91 (m, 2H). 36

2(a) B (Es/AcOEt; Es 90→60%) 443.30 443.2 ¹H NMR (300 MHz, DMSO-d₆) δ10.53 (s, 1H), 8.00 (d, J = 1.98 Hz, 1H), 7.63-7.73 (m, 2H), 7.45-7.61(m, 4H), 7.27-7.41 (m, 3H), 6.53 (s, 1H), 4.89 (t, J = 5.28 Hz, 1H),4.20 (t, J = 6.28 Hz, 2H), 3.63 (q, J = 6.17 Hz, 2H) 37

2(a) B (Es/AcOEt; Es 90→60%) 476.85 477.2 ¹H NMR (300 MHz, DMSO-d₆) δ10.39 (s, 1H), 7.98 (d, J = 1.98 Hz, 1H), 7.73-7.84 (m, 2H), 7.54-7.71(m, 5H), 7.51 (d, J = 8.92 Hz, 1H), 7.36 (dd, J = 2.15, 8.75 Hz, 1H),6.56 (s, 1H), 4.88 (t, J = 6.11 Hz, 1H), 4.21 (t, J = 6.11 Hz, 2H), 3.63(q, J = 6.06 Hz, 2H) 38

2(a) B (Es/AcOEt; Es 90→60%) 460.40 461.4 ¹H NMR (300 MHz, DMSO-d₆) δ10.60 (s, 1H), 7.97 (d, J = 1.98 Hz, 1H), 7.60-7.81 (m, 5H), 7.51 (d, J= 8.92 Hz, 1H), 7.26-7.41 (m, 3H), 6.53 (s, 1H), 4.89 (t, J = 5.45 Hz,1H), 4.20 (t, J = 6.11 Hz, 2H), 3.63 (q, J = 6.17 Hz 2H)

EXAMPLE 3 In Vitro Biological Activity

The test used makes it possible to evaluate the inhibitory capacity ofthe test compounds on the production of PGE₂ and the selectivityrelative to the production of PGF_(2α). The human pulmonaryadenocarcinoma cell line A549 was used, which is particularly sensitiveto stimulation with proinflammatory cytokines, for instance IL-1_(β),and, in response to this stimulation, is particularly active in theproduction and release of two prostanoids: PGE₂ and PGF_(2α) (Thoren S.Jakobsson P-J, 2000).

The cells were stimulated with IL-1_(β) (10 ng/ml) and simultaneouslytreated with the test compound for 22 hours in a suitable culture medium(DMEM Dulbecco's Modified Eagles Medium) enriched with 5% fetal calfserum and L-glutamine (4 mM final) in an incubator at 37° C. and with aCO₂ concentration of 5%.

At the end of the incubation, the amount of PGE₂ and PGF_(2α) producedand released into the supernatant were assayed using an EIA kit(produced and sold by Cayman Chemicals, Ann Arbor, Mich., USA).

The comparative compound used was indomethacin at a concentration of 10nM (Sigma-Aldrich), which is a non-steroidal anti-inflammatory drug thatinhibits in equal measure both PGE₂ and PGF_(2α).

The results, expressed as a percentage of inhibition of the productionof PGE₂ and of PGF_(2α) at a concentration of 10 μM, are given in Table2, in which “ia” (inactive) indicates an inhibitory activity of lessthan 20%.

TABLE 2 % inhibition at 10 μM Compound PGE₂ PGF_(2α) 1 59 ia 7 76 ia 1078 ia 12 78 ia 13 61 ia 21 69 ia 22 94 44 33 41 ia 34 83 44 35 88 13 3640 ia 37 73 ia 38 42 ia Indomethacin (10 nM) 100 100 

For illustrative purposes, Table 3 collates the pIC₅₀ values of a numberof compounds of the invention, where pIC₅₀ represents the negativelogarithm of the IC₅₀, which, in turn, represents the concentration ofcompound that inhibits the production of PGE₂ or PGF_(2α) by 50%relative to cells that are stimulated but not treated with the samecompound.

In Table 3, “nd” means not determinable.

TABLE 3 pIC₅₀ Compound PGE₂ PGF_(2α) 7 5.4 nd 10 5.8 nd 12 5.5 nd 13 5.1nd 21 6.3 nd 22 5.8 4.6 34 5.6 nd 35 5.6 4.5 36 4.3 nd 37 5.2 nd 38 4.6nd Indomethacin 8.3 8.6

EXAMPLE 4 In Vivo Biological Activity

The test compound was evaluated in the model of acetic acid-inducedstretching in mice (Stock J. L. et al., J Clin Inv 2001, 107: 325-331).This test makes it possible to evaluate the antinociceptive activity ofthe compounds of the invention in a model of inflammatory pain.

Female CD-1 mice weighing 25-30 g were used for the test. The animalswere treated intraperitoneally with the test compound (0.1-10 mg/kg)suspended in methylcellulose (MTC). The control animals were treatedwith the vehicle alone (MTC) via the same route.

30 minutes after the treatment, the animals received an intraperitonealinjection of acetic acid (0.7 v/v in physiological solution, 16 μl/g ofbody weight) in order to induce inflammatory pain and to check theeffects of the test compound on the nociceptive response.

Immediately after the administration of acetic acid and for thefollowing 20 minutes, the number of stretches, which represents theparameter for evaluation of the nociceptive response, was measured.

As reported in Table 4, the compound of the invention induced, in adose-dependent manner, a reduction in stretching in the 20 minutesfollowing the administration of acetic acid, compared with the animalstreated with MTC alone.

TABLE 4 Treatment dose (mg/kg) N° of stretches % inhibition Vehicle — 50± 3.3 Compound 10 0.01 47 ± 4.3  5.9 ± 8.76 0.1 34 ± 3.2 33.2 ± 6.16 133 ± 3.9 33.6 ± 8.04 10 21 ± 3.2 57.5 ± 6.57

EXAMPLE 5 Selectivity between Isoforms of PGES

The test used makes it possible to evaluate the capacity of thecompounds of the invention to inhibit the production of PGE₂ in a humanlymphoma cell line U-937 that preferentially expresses an enzymaticisoform (cPGES), which is responsible for the production of PGE₂ underbasal conditions, in the absence of pro-inflammatory stimuli. Thisenzymatic form is different from the one predominantly expressed in theA549 cells (mPGES-1) after a pro-inflammatory stimulus.

The absence of inhibitory activity on PGE₂ in this cell model ensuresthe selectivity of the compound compared with the enzymatic formresponsible for the production of PGE₂ in the presence of inflammatorystimuli.

The results, expressed as a percentage of inhibition of the productionof PGE₂, are given in Table 5, in which “ia” (inactive) indicates aninhibitory activity of less than 20%. The reference compound used wasindomethacin at a concentration of 10 nM.

The compounds of the invention were found not to significantly inhibitthe production of PGE₂ owing mainly to the action of cPGES.

TABLE 5 % inhibition at 10 μM Compound PGE₂ 10 ia 12 ia 13 ia 22 iaIndomethacin (10 nM) 100

The invention claimed is:
 1. An intermediate compound represented byformula (III)

wherein G1, G2, and G3 are a CH group; R1 is a (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₆)alkylOR^(I), (CH₂)_(n)CONR^(II)R^(III),(CH₂)_(n)COR^(I), (CH₂)_(n)COOR^(II), (CH₂)_(n)OCOR^(I), SO₂R^(I),(CH₂)_(n)NR^(II)SO₂R^(I), or (CH₂)_(n)SO₂R^(I) group, optionallysubstituted with 1 to 3 hydroxy groups, wherein n is an integer from 1to 6, R^(I) is a (C₁-C₃)alkyl, or (C₁-C₃)alkylOH group, and R^(II) andR^(III), which may be identical or different, are a hydrogen atom or a(C₁-C₃)alkyl group; W is a σ bond, or a (C₁-C₆)alkyl, (C₂-C₆)alkenyl,O(C₁-C₆)alkyl, O(C₂-C₆)alkenyl, C(O)NH, (CH₂)pCO(CH₂)_(q), or(CH₂)_(p)C(OH)(CH₂)_(q) group, wherein p and q, which may be identicalor different, are an integer from 0 to 3; R2 is a phenyl, pyridyl, or(C₄-C₇)cycloalkyl group, optionally substituted with 1 to 3substituents, which may be identical or different, represented by L-M,wherein L is a σ bond, or a (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkinyl, O(C₁-C₆)alkyl, O(C₂-C₃)alkenyl, or O(C₂-C₆)alkinylgroup, and M is a hydrogen or halogen atom, or a OH, CF₃, NO₂, CN,COOR^(II), SO₂NHR^(II), CH₂CONR^(II)R^(III), NR^(II)R^(III), SO₂R^(IV),NHSO₂R^(IV), POR^(IV)R^(V), or OPOR^(IV)R^(V) group, wherein R^(II) andR^(III), which may be identical or different, have the meaning above,and R^(IV) and R^(V), which may be identical or different, are a(C₁-C₃)alkyl group; and the dotted line between the carbon atoms at the2 and 3 positions means that the bond can be a single bond or a doublebond; provided that when R1 is a (C₁-C₆)alkyl or (C₃-C₇)cycloalkylgroup, optionally substituted with 1 to 3 hydroxy groups, W is a σ bond,and the bond between the carbon atoms in the 2 and 3 position is adouble bond, then R2 is not a phenyl or pyridyl group, optionallysubstituted with 1 to 3 substituents, which may be identical ordifferent, selected from the group consisting of a halogen, (C₁-C₆)alkyloptionally substituted with a hydroxy group, trifluoromethyl, nitro,amino, di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, COOH, COOR^(II),SO₂CH₃, SO₂NHCH₃, NHSO₂CH₃, POR^(IV)R^(V), OPOR^(IV)R^(V),(C₁-C₆)alkyl-COOH, and (C₂-C₆)alkenyl-COOH.
 2. An intermediate compoundaccording to claim 1, wherein R1 is: a (C₁-C₃)alkyl, (C₁-C₃)alkylOR^(I),(CH₂)_(n)NR^(II)R^(III), (CH₂)_(n)CONR^(II)R^(III), (CH₂)_(n)COR^(I),(CH₂)_(n)COOR^(II), (CH₂)_(n)OCOR^(I), SO₂R^(I),(CH₂)_(n)NR^(II)SO₂R^(I), or (CH₂)_(n)SO₂R^(I) group, optionallysubstituted with 1 to 3 hydroxy groups, wherein n is an integer from 1to 4, R^(I) is a (C₁-C₃)alkyl or (C₁-C₃)alkylOH group, and R^(II) andR^(III),which may be identical or different, are a hydrogen atom or a(C₁-C₃)alkyl group; or a (C₁-C₃)alkyl, (C₁-C₃alkylOR^(I),(CH₂)_(n)CONR^(II)R^(III), (CH₂)_(n)COR^(I), (CH₂)_(n)COOR^(II),(CH₂)_(n)OCOR^(I), SO₂R^(I), (CH₂)_(n)NR^(II)SO₂R^(I), or(CH₂)_(n)SO₂R^(I) group, optionally substituted with 1 to 3 hydroxygroups, wherein n is an integer from 1 to 3, R^(I) is a CH₃, C₂H₅,CH₂OH, a C₂H₄OH group, and R^(II) and R^(III), which may be identical ordifferent, are a hydrogen atom or a CH₃, C₂H₅ group.
 3. An intermediatecompound according to claim 1, wherein W is: a σ bond, a (C₁-C₃)alkyl,(C₂-C₄)alkenyl, O(C₁-C₃)alkyl, O(C₂-C₃)alkenyl, C(O)NH,(CH₂)_(p)CO(CH₂)_(q), or (CH₂)_(p)C(OH)(CH₂)_(q) group, wherein p and q,which may be identical or different, are an integer from 1 to 3; or a σbond, a CH₂, C₂H₄, CH═CH, OCH₂, OC₂H₄, OCH═CH, C(O)NH,(CH₂)pCO(CH₂)_(q), or (CH₂)_(p)C(OH)(CH₂)_(q) group, wherein p and q,which may be identical or different, are an integer from 1 to
 2. 4. Anintermediate compound according to claim 1, wherein R2 is: a phenyl,pyridyl, or (C₃-C₇)cycloalkyl group, optionally substituted with 1 to 2substituents, which may be identical or different, represented by anL-M, wherein L is a σ bond, or a (C₁-C₃)alkyl, (C₂-C₄)alkenyl,(C₂-C₄)alkinyl, O(C₁-C₃)alkyl, O(C₂-C₄)alkenyl, or O(C₂-C₄)alkinylgroup, and M is a hydrogen or halogen atom, or a CF₃, CN, COOR^(II),SO₂NHR^(II), CH₂CONR^(II)R^(III), NR^(II)R^(III), SO₂R^(IV),NHSO₂R^(IV), POR^(IV)R^(V), or OPOR^(IV)R^(V) group, wherein R^(II) andR^(III), which may be identical or different, are a hydrogen atom or a(C₁-C₃)alkyl group, and R^(IV) and R^(V), which may be identical ordifferent, are a (C₁-C₃)alkyl group; or a phenyl, pyridyl, or(C₃-C₇)cycloalkyl group, optionally substituted with 1 substituentrepresented by an L-M, wherein L is a σ bond, or a CH₂, C₂H₄, CH═CH,C≡C, OCH₂, OC₂H₄, OCH═CH, OC≡C group, and M is a hydrogen or halogenatom, or a CF₃, CN, COOR^(II), SO₂NHR^(II), CH₂CONR^(II)R^(III),NR^(II)R^(III), SO₂R^(IV), NHSO₂R^(IV), POR^(IV)R^(V), or OPOR^(IV)R^(V)group, wherein R^(II) and R^(III), which may be identical or different,are a hydrogen atom or a CH₃, C₂H₅ group, and R^(IV) and R^(V), whichmay be identical or different, are a CH₃ or C₂H₅ group.
 5. Anintermediate compound according to claim 1, wherein W is σ bond, or aCH₂ or C₂H₄ group; and R2 is a phenyl group optionally substituted with1 to 3 substituents, which may be identical or different, selected fromthe group consisting of Br, Cl, F, CH₃, C₂H₅, OCH₃, OC₂H₅, CN, CH₂CN,and CH₂CONH₂; a cyclohexyl group optionally substituted with 1 to 3substituents, which may be identical or different, selected from thegroup consisting of Br, Cl, F, CH₃, C₂H₅, OCH₃, OC₂H₅, CN, CH₂CN, andCH₂CONH₂; or a pyridyl group optionally substituted with 1 to 3substituents, which may be identical or different, selected from thegroup consisting of Br, Cl, F, CH₃, C₂H₅, OCH₃, OC₂H₅, CN, CH₂CN, andCH₂CONH₂.